1-substituted alkyl-1,2-dihydro-2-pyrazinone derivatives

ABSTRACT

1-Substituted alkyl-1,2-dihydro-2-pyrazinone derivatives of the formula ##STR1## wherein A is lower alkyl; R 1  is selected from the group consisting of alkyl, phenyl-lower alkyl, and substituted phenyl-lower alkyl; R 2  and R 3  are each lower alkyl, or together form tetramethylene and R is selected from the group consisting of hydroxyl, hologen, lower alkanoyloxy R 4  -carbamoyloxy, arylthio, 1-methyltetrazole-5-yl-thio, 1-imidazole, morpholino, ##STR2## in which R 4  is lower alkyl or aryl, R 5  is lhydrogen, lower alkyl or aryl, R 6  is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl, Ar is phenyl or phenyl substituted with C 1-3  alkyl, halogen, nitro, or lower alkoxy, A, R 1 , R 2  and R 3  are as defined above, m is an integer from 4-6, and n is 2 or 3; and pharmaceutically acceptable salts thereof. The compounds are useful as agents for platelet aggregation inhibition, vasodilation and anti-lipoperoxide generation.

BACKGROUND OF THE INVENTION

This invention relates to novel 1-substituted alkyl-2-dihydro pyrazine derivatives and 1-substituted alkyl-2-hexahydro quinoxaline derivatives, which are useful as pharmaceuticals for treating circulatory and metabolic disorders. The compounds of the invention are active as platelet aggregation inhibiting, vasodilating and/or anti-lipoperoxide generating agents.

Recently, a significant number of compounds having platelet aggregation inhibiting activity have been reported. Of these, the only known compounds having a pyrazine ring as the basic structure are tetramethyl pyrazine (16th Heterocyclic Chemistry Symposium (Osaka) pp. 65-68 (1984)) and 2-higher fatty acid acyloxymethyl pyrazine (Jap. Pat. Unexam. Publ. No. 59-219269).

It is of great importance to discover high quality pharmaceuticals having stronger inhibitory activities for platelet aggregation, in order effectively to treat circulatory and metabolic disorders.

We have found that 1-substituted alkyl-2-dihydro pyrazinone derivatives and 1-substituted alkyl-2-hexahydro quinoxaline derivatives display inhibitory action on platelet aggregation, vasodilation activity and/or anti-lipoperoxide generation, and are expected to have excellent pharmaceutical properties.

SUMMARY OF THE INVENTION

In the present invention, a compound of the formula ##STR3## is provided, wherein R is hydroxyl, halogen, lower alkanoyloxy, R₄ -carbamoyloxy, arylthio, 1-methyltetrazole-5-yl-thio, 1-imidazolyl, morpholino, ##STR4## in which R₄ is lower alkyl or aryl, R₅ is hydrogen, lower alkyl or aryl, R₆ is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl, A and A₁ are lower alkylene, m is an integer of 4-6, n is an integer of 2-3, the above aryl is phenyl or phenyl substituted with C₁₋₃ alkyl, halogen, nitro or lower alkoxy, R₁ is alkyl, phenyl-lower alkyl optionally having substituent, R₂ and R₃ are each lower alkyl, or together form tetramethylene.

The compound [1] can be provided in salt form. The salts must be pharmacologically acceptable non-toxic salts thereof. Examples of such salts are salts of an inorganic acid such as hydrochloric, sulfuric, or phosphoric, and salts of an organic acid such as acetic, propionic, butyric, glycolic, gluconic, malic, tartaric, succinic, mandelic, aspartic, glutaric, methanesulfonic or toluenesulfonic. Salts of other known acids can be used as well.

DETAILED DESCRIPTION OF THE INVENTION

The compound [1] can be produced by the following processes:

Process A:

A process for production of compound [1] wherein R is hydroxyl, and the compound produced thus has the formula ##STR5## wherein R₁, R₂, R₃ and A are defined as above.

The above compound [1a] can be produced by reacting a compound of the formula ##STR6## where R₁, R₂ and R₃ are defined as above, with a hydroxyalkyl halide of the formula

    X--A--OH

where X is halogen and A is defined as above, in an organic solvent.

In the compound [2] above, R₁ is alkyl, optionally substituted phenyl, or optionally substituted phenyl-lower alkyl. "Alkyl", as used above, is defined as saturated or unsaturated C₁₋₂₀ alkyl, which may be branched or unbranched. Examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl or hexadecyl. "Optionally substituted phenyl", as used above, is defined as phenyl or phenyl substituted with C₁₋₃ lower alkyl, halogen, nitro, or lower alkoxy. "Optionally substituted phenyl-lower alkyl", as used above, is defined as phenyl or phenyl substituted with C₁₋₃ lower alkyl, halogen, nitro or lower alkoxy, in which lowere alkyl means methyl, 2-ethyl, 1-ethyl, 3-propyl or 1-propyl. Examples are benzyl, p-chlorobenzyl, 2-phenylethyl and 1-phenylethyl.

In the compound [2] above, R₂ and R₃ are each lower alkyl, or together form tetramethylene. The lower alkyl can be methyl, ethyl or propyl. The compound [2] wherein R₂ and R₃ together form tetramethylene can be designated as 2-hydroxy-3-substituted-hexahydro quinoxaline. Among the class of compounds [2] in which R₂ and R₃ are lower alkyl, i.e. 2-hydroxy-3-substituted-5,6-di(lower alkyl)pyrazine, some examples have been reported. These compounds can be produced by a process or an improvement thereto as disclosed in J. Am. Chem. Soc., 71: 78-81 (1949) and ibid: 74: 1580-1583 (1952). Novel derivatives thereof can also be produced according to the methods described in the above references. The compound [2] wherein R₂ and R₃ together form tetramethylene, i.e. 2-hydroxy-3-substituted-hexahydro quinoxaline derivatives, is produced by the process developed by the present inventors, in which an α-amino acidamide, other than glycine, is reacted with 1,2-cyclohexanedione in an alkaline medium.

The group A in the above hydroxylalkyl halide is defined as above, namely, lower alkylene. Examples of lower alkylene are methylene, ethylene, methylmethylene, propylene, 1-methylethylene, 1,1-dimethylmethylene or 1-ethylmethylene; ethylene is preferred.

The group X in the above hydroxyalkyl halide is halogen, such as chlorine or bromine, and in general chlorine is preferred. The preferred hydroxyalkyl halide is ethylene chlorohydrin.

Reaction of the compound [2] with hydroxyalkyl halide proceeds in an organic solvent such as butanol.

The above reaction is preferably effected in an aqueous alkali solvent such as hydroxy alkali, and preferably, is possible, under heating. Isolation of the product [1a] can be performed by adding water to the reaction mixture and extracting with water-immiscible organic solvent.

Process B:

A process for production of compound [1] wherein R is lower alkanoyloxy (hereinafter designated as compound [1b]):

A compound [1b] can be produced by acylating an above compound [1a] with lower fatty acid or its reactive derivative.

Examples of lower fatty acid are branched or unbranched C₁₋₆ fatty acids such as acetic acid, propionic acid, butyric acid, isobutyric acid, sec-butyric acid, valeric acid, isovaleric acid and hexanoic acid. Examples of reactive derivatives are known acylating agents for the hydroxyl group, such as acid halide, acid anhydride, mixed anhydride or active ester. The lower fatty acid can itself be acylated in the presence of a condensation reagent such as N,N-dicyclohexyl carbodiimide (DCC).

In the above reactions, co-generated acid can be removed by an acid-binder, for example a known tertiary organic amine such as pyridine or triethylamine.

The product [1b] can be isolated by pouring the reaction mixture into dilute aqueous alkali and extracting with water-immiscible organic solvent.

Process C:

A process for production of compound [1] wherein R is R₄ -carbamoyloxy (hereinafter designated as a compound [1c]):

A compound [1c] can be produced by reacting the above compound [1a] with lower alkyl isocyanate or aryl isocyanate.

"Lower alkyl" in the above lower alkyl carbamoyloxy means branched or unbranched C₁₋₆ alkyl, and "aryl" in the above aryl carbamoyloxy means phenyl or phenyl substituted with C₁₋₃ lower alkyl, halogen, nitro or lower alkoxy.

Reaction of the compound [1a] and the isocyanate compound proceeds in an organic solvent such as pyridine. Isolation of the product [1c] can be effected by removing solvent from the reaction mixture and extracting the resultant residue with an inert organic solvent in an aqueous medium, or precipitating the product [1c] by adding solvent such as ether.

Process D:

A process for production of compound [1] wherein R is halogen, and the compound produced thus has the formula ##STR7## wherein X is halogen, and A, R₁, R₂ and R₃ are defined as above.

A compound [1d] can be produced by halogenating the compound [1a] above with halogenating agent.

The said halogenating agent may be any known halogenating agent. More specifically, known chlorination reagents or bromination reagents can be used. Conventional chlorination reagents such as SOCl₂, PCl₅ and POCl₃ can be applied. The halogenation reaction can be effected, in general, in an inert organic solvent such as chloroform. Reaction proceeds at room temperature. Isolation of the product [1d] can be performed by adding a water-immiscible organic solvent such as chloroform, washing with dilute aqueous alkali, dehydrating the organic layer and removing the solvent therefrom.

The compound [1d] can be used without purification, as by silica-gel column chromatography, as an intermediate in the synthesis of compounds [1e] and [1f] below.

Process E:

A process for production of compound [1] wherein R is arylthio or 1-methyltetrazole-5-yl-thio (hereinafter designated as compound [1e]):

A compound [1e] can be produced by reacting the above compound [1d] with an alkali metal salt of arylmercaptan or an alkali metal salt of 1-methyl-5-mercaptotetrazole in an organic solvent.

"Aryl" in the above arylthio means phenyl or phenyl substituted with C₁₋₃ lower alkyl, halogen, nitro or lower alkoxy.

Examples of the above alkali salts of arylmercaptan or 1-methyl-5-mercaptotetrazole are the corresponding sodium and potassium salts.

Reaction of the above compound [1d] and the said alkali metal salt of the mercapto compound proceeds, in general, in an organic solvent such as dimethyl formamide (DMF). Isolation of the product [1e] can be performed by removing the reaction solvent and extracting the residue with water-immiscible organic solvent in the presence of dilute aqueous alkali.

Process F:

A process for production of compound [1] wherein R is a group other than hydroxyl, halogen, lower alkanoyloxy, R₄ -carbamoyloxy, arylthio and 1-methyltetrazole-5-yl-thio (hereinafter designated as compound [1f]):

A compound [1f] can be produced by reacting a compound [1d] with an amine of the formula

    R'--H

wherein R' is 1-imidazolyl, morpholino, ##STR8## and R₁, R₂, R₃, R₅, R₆, A, A₁, m and n are defined as above. ##STR9## wherein m is an integer of 4-6, is defined as pyrrolidine, piperidine or hexamethyleneimine ring. R₅ means hydrogen, lower alkyl or aryl. The position of the R₅ group may be any position in the ring hereinabove except at position 1 (nitrogen). The above alkyl means branched or unbranched C₁₋₆ alkyl. "Aryl" as used above means phenyl or phenyl substituted with C₁₋₃ lower alkyl, halogen, nitro or lower alkoxy.

The group R₆ in the above ##STR10## is defined as hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl. Examples of the above alkyl are branched or unbranched C₁₋₄ alkyl such as methyl, 2-ethyl, 1-ethyl, propyl, isopropyl and 1-methylethyl. Examples of aryl are phenyl; or phenyl substituted with C₁₋₃ alkyl, halogen, nitro or lower alkoxy, such as tolyl, xylyl, p(m or o)-nitrophenyl, p(m or o)-fluorophenyl, 2,4(2,3-, 3,4-, 2,5-, 3,5- or 2,6-)-dichlorophenyl, p(m or o)-nitrophenyl, p(m or o)-methoxyphenyl, 2,3(2,4-, 3,4-, 2,5-, 3,5- or 2,6)-dimethoxyphenyl. The above lower alkanoyl is branched or unbranched C₂₋₄ alkanoyl such as acetyl, propionyl, butyryl, isobutyryl or sec-butyryl.

The ring of the group ##STR11## wherein N is integer of 2-3, is piperazine or homopiperazine. A₁ is lower alkylene such as methylene, ethylene, methylmethylene, propylene, 1-methylethylene or 1-ethylmethylene, and preferred examples are methylene and ethylene. "Aryl" as used above means phenyl or phenyl substituted with C₁₋₃ lower alkyl, halogen, nitro or lower alkoxy. Examples thereof have been set forth above.

Accordingly, specific examples of the amine (R'--H) are 1-imidazole, morpholine, pyrrolidine, piperidine, 4-methylpiperazine, 4-ethylpiperazine, 4-butylpiperazine, 4-(2-hydroxyethyl)-piperazine, 4-phenyl-piperazine, 4-(o-chlorophenyl)-piperazine, 4-(o-methoxyphenyl)-piperazine, 4 (phenylacetyl)-piperazine, 4-benzoyl-piperazine, 4-(p-chlorobenzoyl)-piperazine, 4-(p-nitrobenzoyl)-piperazine, 4-(p-methoxybenzoyl)-piperazine, 4-(2,3-dimethoxybenzoyl)-piperazine, 4-(2,4-dimethoxybenzoyl)-piperazine, 4-(3,4-dimethoxybenzoyl)-piperazine, 4-(3,4,5-trimethoxybenzoyl)-piperazine, 4-benzenesulfonyl-piperazine, 4-(p-chlorobenzenesulfonyl)-piperazine, 4-(2-thienylacetyl)-piperazine, 4-benzyl-piperazine, 4-(p-methylbenzyl)-piperazine, 4-(p-chlorobenzyl)-piperazine, 4-(m-chlorobenzyl)-piperazine, 4-(o-chlorobenzyl)-piperazine, 4-(2,4-dichlorobenzyl)-piperazine, 4-(p-fluorobenzyl)-piperazine, 4-(p-nitrobenzyl)-piperazine, 4-(p-methoxybenzyl)-piperazine, 4-benzyl-homopiperazine, 4-(p-methylbenzyl)-homopiperazine, 4-(p-chlorobenzyl)-homopiperazine, 4-(p-fluorobenzyl)-homopiperazine, 4-(p-nitrobenzyl)-homopiperazine and 4-(p-methoxybenzyl)-homopiperazine. Reaction of the compound [1d] and the above amine ordinarily proceeds in an inert organic solvent such as benzene, under heating. In the reaction, hydrogen halogenide is generated so that the said reaction proceeds in the presence of acid binder, for example known tertiary organic amines such as triethylamine. The compound [1f] can be isolated by pouring the reaction mixture into dilute aqueous alkali and extracting with water-immiscible organic solvent such as benzene or chloroform.

Process G:

A process for production of compound [1] wherein R is ##STR12## in which R₆ is aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl, or thienyl-lower alkanoyl (hereinafter designated as compound [1g]).

A compound [1g] can be produced by Process F above, but is also produced by means of another method in which a compound of the formula ##STR13## wherein R₁, R₂, R₃ and A have the same meanings hereinbefore, is acylated with an organic acid or a reactive derivative thereof.

The above organic acid is aryl-lower fatty acid, arylcarboxylic acid, arylsulfonic acid or thienyl-lower fatty acid, in which aryl means phenyl or phenyl substituted with C₁₋₃ alkyl, halogen, nitro or lower alkoxy, and lower fatty acid means a branched or unbranched C₁₋₄ fatty acid, for example acetic acid, propionic acid, butyric acid, isobutyric acid or sec-butyric acid. Examples of organic acid are phenyl-acetic acid, benzoic acid, p-chlorobenzoic acid, p-nitrobenzoic acid, p-methoxybenzoic acid, 2,3-dimethoxy benzoic acid, 2,4-dimethoxybenzoic acid, 3,4-dimethoxybenzoic acid, 3,4,5-trimethoxybenzoic acid, benzenesulfonic acid, p-toluenesulfonic acid and 2-thienylacetic acid. Examples of reactive derivatives are known acylating agents for the amino group, for example acid halide, acid anhydride, mixed anhydride and activated ester. Also, the organic acid can itself be acylated in the presence of a condensation agent such as DCC. Because acid is co-generated in the reaction, the reaction may proceed in the presence of an acid binder, for example known tertiary organic amines such as pyridine or triethylamine. The acylating reaction proceeds in a conventional organic solvent. The produced compound [1g] can be isolated by pouring the reaction mixture into dilute aqueous alkali and extracting with a water-immiscible organic solvent.

The thus-obtained compound [1] is purified, if required, by column chromatography using silica-gel, activated alumina or adsorption resin with elution solvent such as chloroform-methanol or benzene-ethyl acetate.

A compound [1] is generally produced in the form of its free base, but it can also be produced in the form of a conventional salt thereof. For example, a hydrochloride can be prepared by dissolving a compound [1] in a lower alcohol such as methanol or ethanol, adding a slight molar excess of hydrochloric acid, and isolating the precipitated material, or if not precipitated, by adding ether therein to precipitate. The molar ratio of hydrochloric acid may be different according to the specific compound [1].

Examples of the compound [1] of the present invention are set forth in Table 1.

                                      TABLE 1                                      __________________________________________________________________________      ##STR14##                                                                     Compound No.                                                                           R.sub.1  R.sub.2                                                                            R.sub.3                                                                           A      R                                               __________________________________________________________________________     018     Me       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR15##                                      019     Me       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR16##                                      020     Me       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR17##                                      021     Me       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR18##                                      022     Me       Me  Me CH.sub.2 CH.sub.2                                                                     1-imidazolyl                                    023     Me       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR19##                                      024     Me       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR20##                                      025     Me       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR21##                                      026     Me       Me  Me CH.sub.2 CH.sub.2                                                                     OH                                              027     Me       Me  Me CH.sub.2 CH.sub.2                                                                     SPh                                             028     Me       Me  Me CH.sub.2 CH.sub.2                                                                     S(1-methyltetrazole-5-yl)                       061     Me       Me  Me CH.sub.2 CH.sub.2                                                                     OCOMe                                           062     Me       Me  Me CH.sub.2 CH.sub.2                                                                     OCONHMe                                         063     Me       Me  Me CH.sub.2 CH.sub.2                                                                     OCONHPh                                         064     Me       Me  Me CH.sub.2 CH.sub.2                                                                     OCONHPhCl(p)                                    101     Me       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR22##                                      109     Ph       Me  Me CH.sub.2 CH.sub.2                                                                     OH                                              110     Ph       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR23##                                      111     Ph       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR24##                                      112     CH.sub.2 Ph                                                                             Me  Me CH.sub.2 CH.sub.2                                                                     OH                                              113     CH.sub.2 Ph                                                                             Me  Me CH.sub.2 CH.sub.2                                                                      ##STR25##                                      114     CH.sub.2 Ph                                                                             Me  Me CH.sub.2 CH.sub.2                                                                      ##STR26##                                      115     CH.sub.2 Ph                                                                             Me  Me CH.sub.2 CH.sub.2                                                                      ##STR27##                                      116     CH.sub.2 Ph                                                                             Me  Me CH.sub.2 CH.sub.2                                                                      ##STR28##                                      117     Pro      (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR29##                                      118     Pro      (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR30##                                      119     Pro      (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR31##                                      120     Pro      (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR32##                                      121     Pro      Me  Me CH.sub.2 CH.sub.2                                                                      ##STR33##                                      122     Pro      Me  Me CH.sub.2 CH.sub.2                                                                      ##STR34##                                      123     iso-Bu   Me  Me CH.sub.2 CH.sub.2                                                                      ##STR35##                                      124     iso-Bu   Me  Me CH.sub.2 CH.sub.2                                                                      ##STR36##                                      125     iso-Bu   Me  Me CH.sub.2 CH.sub.2                                                                      ##STR37##                                      126     iso-Bu   Me  Me CH.sub.2 CH.sub.2                                                                      ##STR38##                                      127     iso-Bu   (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR39##                                      128     iso-Bu   (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR40##                                      129     iso-Bu   (CH.sub.2 ).sub.4                                                                     CH.sub.2 CH.sub.2                                                                      ##STR41##                                      130     Pro      Et  Et CH.sub.2 CH.sub.2                                                                      ##STR42##                                      131     Pro      Et  Et CH.sub.2 CH.sub.2                                                                      ##STR43##                                      132     Pro      Et  Et CH.sub.2 CH.sub.2                                                                      ##STR44##                                      133     Pro      Et  Et CH.sub.2 CH.sub.2                                                                      ##STR45##                                      134     Pro      Et  Et CH.sub.2 CH.sub.2                                                                      ##STR46##                                      141     Bu       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR47##                                      142     Bu       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR48##                                      143     Bu       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR49##                                      144     Bu       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR50##                                      145     Bu       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR51##                                      146     Bu       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR52##                                      147     CH.sub.2 Ph                                                                             Me  Me CH.sub.2 CH.sub.2                                                                     OCOMe                                           148     iso-Pro  Me  Me CH.sub.2 CH.sub.2                                                                      ##STR53##                                      149     iso-Pro  Me  Me CH.sub.2 CH.sub.2                                                                      ##STR54##                                      150     iso-Pro  Me  Me CH.sub.2 CH.sub.2                                                                      ##STR55##                                      151     iso-Pro  Me  Me CH.sub.2 CH.sub.2                                                                      ##STR56##                                      152     sec-Bu   Me  Me CH.sub.2 CH.sub.2                                                                      ##STR57##                                      153     sec-Bu   Me  Me CH.sub.2 CH.sub.2                                                                      ##STR58##                                      154     sec-Bu   Me  Me CH.sub.2 CH.sub.2                                                                      ##STR59##                                      155     sec-Bu   Me  Me CH.sub.2 CH.sub.2                                                                      ##STR60##                                      156     Bu       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR61##                                      157     Bu       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR62##                                      158     Bu       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR63##                                      159     iso-Pro  Et  Et CH.sub.2 CH.sub.2                                                                      ##STR64##                                      160     iso-Pro  Et  Et CH.sub.2 CH.sub.2                                                                      ##STR65##                                      161     iso-Pro  Et  Et CH.sub.2 CH.sub.2                                                                      ##STR66##                                      162     iso-Pro  Et  Et CH.sub.2 CH.sub.2                                                                      ##STR67##                                      163     iso-Pro  Et  Et CH.sub.2 CH.sub.2                                                                      ##STR68##                                      164     iso-Pro  Et  Et CH.sub.2 CH.sub.2                                                                      ##STR69##                                      165     iso-Pro  Et  Et CH.sub.2 CH.sub.2                                                                      ##STR70##                                      166     iso-Bu   Et  Et CH.sub.2 CH.sub.2                                                                      ##STR71##                                      167     iso-Bu   Et  Et CH.sub.2 CH.sub.2                                                                      ##STR72##                                      168     iso-Bu   Et  Et CH.sub.2 CH.sub.2                                                                      ##STR73##                                      170     iso-Bu   Et  Et CH.sub.2 CH.sub.2                                                                      ##STR74##                                      171     sec-Bu   Et  Et CH.sub.2 CH.sub.2                                                                      ##STR75##                                      172     sec-Bu   Et  Et CH.sub.2 CH.sub.2                                                                      ##STR76##                                      173     sec-Bu   Et  Et CH.sub.2 CH.sub.2                                                                      ##STR77##                                      174     sec-Bu   Et  Et CH.sub.2 CH.sub.2                                                                      ##STR78##                                      175     sec-Bu   Et  Et CH.sub.2 CH.sub.2                                                                      ##STR79##                                      176     sec-Bu   Et  Et CH.sub.2 CH.sub.2                                                                      ##STR80##                                      177     sec-Bu   Et  Et CH.sub.2 CH.sub.2                                                                      ##STR81##                                      178              Et  Et CH.sub.2 CH.sub.2                                                                      ##STR82##                                      179     Bu       Et  Et CH.sub.2 CH.sub.2                                                                      ##STR83##                                      180     Bu       Et  Et CH.sub.2 CH.sub.2                                                                      ##STR84##                                      181     Bu       Et  Et CH.sub.2 CH.sub.2                                                                      ##STR85##                                      182     Bu       Et  Et CH.sub.2 CH.sub.2                                                                      ##STR86##                                      183     Bu       Et  Et CH.sub.2 CH.sub.2                                                                      ##STR87##                                      185     Bu       Et  Et CH.sub.2 CH.sub.2                                                                      ##STR88##                                      187     Et       Et  Et CH.sub.2 CH.sub.2                                                                      ##STR89##                                      188     Et       Et  Et CH.sub.2 CH.sub.2                                                                      ##STR90##                                      189     Et       Et  Et CH.sub.2 CH.sub.2                                                                      ##STR91##                                      190     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR92##                                      191     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR93##                                      192     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR94##                                      193     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR95##                                      250     (CH.sub.2).sub.4 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR96##                                      251     (CH.sub.2).sub.4 CH.sub.3                                                                (CH.sub.2).sub.4                                                                     CH.sub.2 CH.sub.2                                                                      ##STR97##                                      252     (CH.sub.2).sub.4 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR98##                                      253     (CH.sub.2).sub.4 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR99##                                      254     (CH.sub.2).sub.4 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR100##                                     255     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR101##                                     256     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR102##                                     257     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR103##                                     258     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR104##                                     259     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR105##                                     260     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR106##                                     261     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR107##                                     262     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2 ).sub.4                                                                     CH.sub.2 CH.sub.2                                                                      ##STR108##                                     263     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR109##                                     264     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR110##                                     265     (CH.sub.2).sub.7 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR111##                                     266     (CH.sub.2).sub.7 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR112##                                     267     (CH.sub.2).sub.7 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR113##                                     268     (CH.sub.2).sub.7 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR114##                                     269     (CH.sub.2).sub.7 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR115##                                     270     (CH.sub.2).sub.7 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR116##                                     271     (CH.sub.2).sub.8 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR117##                                     272     (CH.sub.2).sub.8 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR118##                                     273     (CH.sub.2).sub.8 CH.sub.3                                                                (CH.sub.2).sub.4                                                                     CH.sub.2 CH.sub.2                                                                      ##STR119##                                     274     (CH.sub.2).sub.8 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR120##                                     275     (CH.sub.2).sub.8 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR121##                                     276     (CH.sub.2).sub.11 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR122##                                     277     (CH.sub.2).sub.11 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR123##                                     278     (CH.sub.2).sub.11 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR124##                                     279     (CH.sub.2).sub.11 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR125##                                     280     (CH.sub.2).sub.13 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR126##                                     281     (CH.sub.2).sub.13 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR127##                                     282     (CH.sub.2).sub.13 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR128##                                     283     (CH.sub.2).sub.15 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR129##                                     284     (CH.sub.2).sub.15 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR130##                                     285     (CH.sub.2).sub.15 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR131##                                     286     (CH.sub.2).sub.15 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR132##                                     287     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR133##                                     288     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR134##                                     289     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR135##                                     290     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR136##                                     291     CH.sub.2 Ph                                                                             Et  Et CH.sub.2 CH.sub.2                                                                      ##STR137##                                     292     CH.sub.2 Ph                                                                             Et  Et CH.sub.2 CH.sub.2                                                                      ##STR138##                                     293     CH.sub.2 Ph                                                                             Et  Et CH.sub.2 CH.sub.2                                                                      ##STR139##                                     294     CH.sub.2 Ph                                                                             Et  Et CH.sub.2 CH.sub.2                                                                      ##STR140##                                     295     CH.sub.2 Ph                                                                             Et  Et CH.sub.2 CH.sub.2                                                                      ##STR141##                                     296     CH.sub.2 Ph                                                                             Et  Et CH.sub.2 CH.sub.2                                                                      ##STR142##                                     297     CH.sub.2 Ph                                                                             Et  Et CH.sub.2 CH.sub.2                                                                      ##STR143##                                     305     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR144##                                     306     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR145##                                     307     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR146##                                     308     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR147##                                     309     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR148##                                     310     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR149##                                     311     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR150##                                     312     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR151##                                     313     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR152##                                     314     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR153##                                     315     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR154##                                     316     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR155##                                     317     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR156##                                     318     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR157##                                     319     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR158##                                     320     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR159##                                     321     (CH.sub.2).sub.7 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR160##                                     322     (CH.sub.2).sub.7 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR161##                                     323     (CH.sub.2).sub.7 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR162##                                     324     (CH.sub.2).sub.7 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR163##                                     325     (CH.sub.2).sub.7 CH.sub.3                                                                (CH.sub.2).sub.4                                                                     CH.sub.2 CH.sub.2                                                                      ##STR164##                                     326     (CH.sub.2).sub.7 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR165##                                     327     (CH.sub.2).sub.7 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR166##                                     328     (CH.sub.2).sub.8 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR167##                                     329     (CH.sub.2).sub.8 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR168##                                     330     (CH.sub.2).sub.8 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub. 2 CH.sub.2                                                                     ##STR169##                                     331     (CH.sub.2).sub.8 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR170##                                     332     (CH.sub.2).sub.8 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR171##                                     334     (CH.sub.2).sub.9 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR172##                                     335     (CH.sub.2).sub.9 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR173##                                     336     (CH.sub.2).sub.9 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR174##                                     337     (CH.sub.2).sub.9 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR175##                                     338     (CH.sub.2).sub.9 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR176##                                     339     (CH.sub.2).sub.9 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR177##                                     340     (CH.sub.2).sub.9 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR178##                                     374     CH.sub.2 Ph                                                                             Et  Et CH.sub.2 CH.sub.2                                                                      ##STR179##                                     375     CH.sub.2 Ph                                                                             Et  Et CH.sub.2 CH.sub.2                                                                      ##STR180##                                     378     CH.sub.2 Ph                                                                             Et  Et CH.sub.2 CH.sub.2                                                                      ##STR181##                                     380     CH.sub.2 Ph                                                                             Et  Et CH.sub.2 CH.sub.2                                                                      ##STR182##                                     384     CH.sub.2 PhCl(p)                                                                        Et  Et CH.sub.2 CH.sub.2                                                                      ##STR183##                                     385     CH.sub.2 PhCl(p)                                                                        Et  Et CH.sub.2 CH.sub.2                                                                      ##STR184##                                     386     CH.sub.2 PhCl(p)                                                                        Et  Et CH.sub.2 CH.sub.2                                                                      ##STR185##                                     387     CH.sub.2 PhCl(p)                                                                        Et  Et CH.sub.2 CH.sub.2                                                                      ##STR186##                                     454     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR187##                                     455     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR188##                                     456     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR189##                                     457     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR190##                                     458     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR191##                                     459     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR192##                                     460     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR193##                                     461     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR194##                                     462     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR195##                                     463     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR196##                                     464     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR197##                                     465     Et       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR198##                                     467     CH.sub.2 PhCl(p)                                                                        Et  Et CH.sub.2 CH.sub.2                                                                      ##STR199##                                     470     CH.sub.2 Ph                                                                             (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR200##                                     471     CH.sub.2 Ph                                                                             (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR201##                                     472     CH.sub.2 Ph                                                                             (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR202##                                     473     CH.sub.2 Ph                                                                             (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR203##                                     474     CH.sub.2 Ph                                                                             (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR204##                                     475     CH.sub.2 Ph                                                                             (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR205##                                     476     CH.sub.2 CH.sub.2 Ph                                                                    (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR206##                                     477     CH.sub.2 CH.sub.2 Ph                                                                    (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR207##                                     478     CH.sub.2 CH.sub.2 Ph                                                                    (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR208##                                     479     CH.sub.2 CH.sub.2 Ph                                                                    (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR209##                                     480     CH.sub.2 CH.sub.2 Ph                                                                    (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR210##                                     481     Et       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR211##                                     482     Et       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR212##                                     483     Et       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR213##                                     484     Et       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR214##                                     485     Et       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR215##                                     486     Et       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR216##                                     487     (CH.sub.2).sub.13 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR217##                                     488     (CH.sub.2).sub.13 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR218##                                     489     (CH.sub.2).sub.13 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR219##                                     490     (CH.sub.2).sub.13 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR220##                                     611     Me       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR221##                                     612     Ph       Me  Me CH.sub.2 CH.sub.2                                                                     Cl                                              613     CH.sub.2 Ph                                                                             Me  Me CH.sub.2 CH.sub.2                                                                     Cl                                              614     Pro      (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              615     Pro      (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     SPh                                             616     Pro      Me  Me CH.sub.2 CH.sub.2                                                                     OH                                              617     iso-Bu   Me  Me CH.sub.2 CH.sub.2                                                                     OH                                              618     iso-Bu   (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              619     iso-Bu   Me  Me CH.sub.2 CH.sub.2                                                                      ##STR222##                                     620     Pro      Et  Et CH.sub.2 CH.sub.2                                                                     OH                                              621     Bu       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              622     iso-Pro  Me  Me CH.sub.2 CH.sub.2                                                                     OH                                              623     sec-Bu   Me  Me CH.sub.2 CH.sub.2                                                                     OH                                              624     Bu       Me  Me CH.sub.2 CH.sub.2                                                                     OH                                              625     iso-Pro  Et  Et CH.sub.2 CH.sub.2                                                                     OH                                              626     iso-Bu   Et  Et CH.sub.2 CH.sub.2                                                                     OH                                              627     sec-Bu   Et  Et CH.sub.2 CH.sub.2                                                                     OH                                              628     Bu       Et  Et CH.sub.2 CH.sub.2                                                                     OH                                              629     Et       Et  Et CH.sub.2 CH.sub.2                                                                     OH                                              630     Et       Me  Me CH.sub.2 CH.sub.2                                                                     OH                                              631     (CH.sub.2).sub.4 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              632     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              633     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              634     (CH.sub.2).sub.7 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              635     (CH.sub.2).sub.8 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              636     (CH.sub.2).sub.9 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              637     (CH.sub.2).sub.11 CH.sub.3                                                              (CH.sub.2).sub.4                                                                       CH.sub.2 CH.sub.2                                                                    OH                                              638     (CH.sub.2).sub.13 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              639     (CH.sub.2).sub.15 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              640     CH.sub.2 Ph                                                                             Et  Et CH.sub.2 CH.sub.2                                                                     OH                                              641     CH.sub.2 PhCl(p)                                                                        Et  Et CH.sub.2 CH.sub.2                                                                     OH                                              642     Me       Me  Me CH.sub.2 CH.sub.2                                                                      ##STR223##                                     643     CH.sub.2 Ph                                                                             (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              644     CH.sub.2 Ph                                                                             (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     Cl                                              645     CH.sub.2 CH.sub.2 Ph                                                                    (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              646     Et       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              647     CH.sub.2 PhCl(p)                                                                        Et  Et CH.sub.2 CH.sub.2                                                                     Cl                                              __________________________________________________________________________      Me; methyl                                                                     Et; ethyl                                                                      Pro; propyl                                                                    iso-Pro; isopropyl                                                             Bu; butyl                                                                      iso-Bu; isobutyl                                                               sec-Bu; secbutyl                                                               Ph; benzene ring                                                               ##STR224##                                                                     ##STR225##                                                                     ##STR226##                                                                     ##STR227##                                                                     A letter or number in ( ) indicates the position of the preceding              substituent.                                                             

The pharmacological acitvity of the present compounds [1] is illustrated below. All the compounds [1] used in the pharmacological tests were tested in the form of the hydrochloride salt thereof.

1. Platelet aggregation inhibition:

Sample solution containing a compound [1] (final concentration 500 or 100 μM) is added to rabbit platelet plasma to which was added 10% by volume of a 3.8% sodium citrate solution, and the mixture is incubated at 37° C. for 3 mins. A platelet activation factor (PAF, final concentration 10-50 ng/ml) or collagen (final concentration 2.5 μg/ml) is added thereto as an aggregating agent, and platelet aggregation activity is measured with an aggrigometer. The results of assays for PAF-induced aggregation are shown in Table 2, and those for collagen-induced aggregation are shown in Table 3, which tables show the strong platelet aggregation inhibitory activity of the compounds [1] of the present invention.

                  TABLE 2                                                          ______________________________________                                         Platelet Aggregation Inhibitory Action on                                      PAF-Induced Aggregation                                                        Compound      Concentration                                                                              Inhibition                                           No.           μ M      %                                                    ______________________________________                                         114           500         63                                                   115           "           88                                                   116           "           76                                                   120           "           83                                                   126           "           54                                                   128           "           83                                                   129           "           79                                                   132           "           72                                                   133           "           63                                                   134           "           57                                                   142           "           82                                                   143           "           87                                                   145           "           52                                                   146           "           87                                                   154           "           54                                                   158           "           64                                                   160           "           97                                                   161           "           93                                                   162           "           93                                                   163           "           62                                                   165           "           92                                                   166           "           87                                                   168           "           76                                                   170           "           80                                                   172           "           57                                                   173           "           61                                                   174           "           96                                                   175           "           94                                                   176           "           81                                                   177           "           79                                                   178           "           94                                                   179           "           93                                                   180           "           90                                                   183           "           85                                                   185           "           61                                                   188           "           86                                                   189           "           69                                                   191           "           62                                                   253           100         93                                                   263           "           70                                                   306           "           60                                                   308           "           40                                                   310           "           46                                                   313           "           48                                                   316           "           49                                                   321           "           43                                                   323           "           43                                                   326           "           51                                                   332           "           46                                                   386           "           71                                                   387           "           41                                                   ______________________________________                                    

                  TABLE 3                                                          ______________________________________                                         Platelet Aggregation Inhibitory Action on                                      Collagen-Induced Aggregation                                                   Compound      Concentration                                                                              Inhibition                                           No.           μ M      %                                                    ______________________________________                                         114           100         50                                                   115           "           50                                                   251           "           78                                                   252           "           42                                                   253           "           52                                                   255           "           48                                                   263           "           73                                                   265           "           45                                                   287           "           50                                                   288           "           72                                                   289           "           58                                                   292           "           50                                                   384           "           76                                                   386           "           71                                                   467           "           80                                                   471           "           81                                                   473           "           64                                                   474           "           81                                                   475           "           81                                                   477           "           72                                                   ______________________________________                                    

2. Vasodilation activity:

A dog, pretreated with morphine (81.5 mg/kg, sc) is anesthetized with urethane (8450 mg/kg, iv) and α-chloralose (45 mg/kg, iv), and immobilized in the dosal position. Right femoral arterial blood is introduced into a left femoral artery via a perfusion pump, and Sterling's resistance is connected to the exosomatic circulatory system to perfuse blood to a left back limb at constant pressure. The perfusion pressure is set with a valve at slightly higher than that of the average blood pressure of the animal. Sample (100 μg) dissolved in physiological saline solution is administered to a right femoral artery, and changes in blood flow are measured. Vasodilation activity is measured as a relative activity, by defining as 100% the increased rate of blood flow when 30 μg papaverine is administered intra-arterially. The results are shown in Table 4, where it will be seen that the compounds [1] of the present invention have strong vasodilation activity.

                  TABLE 4                                                          ______________________________________                                         Vasodilation Activity                                                                         Vasodilation                                                    Compound No.   activity %                                                      ______________________________________                                         023            118                                                             024            182                                                             025            112                                                             114            174                                                             115            210                                                             116            147                                                             119            132                                                             120            223                                                             122            161                                                             124            278                                                             125            220                                                             126            310                                                             128            155                                                             129            201                                                             131            158                                                             132            231                                                             133            251                                                             134            143                                                             142            151                                                             143            119                                                             144            120                                                             146            125                                                             149            122                                                             150            229                                                             151            121                                                             153            197                                                             157            162                                                             158            139                                                             160            117                                                             161            214                                                             162            212                                                             165            222                                                             166            153                                                             168            205                                                             170            178                                                             171            122                                                             174            179                                                             175            151                                                             176            159                                                             177            122                                                             178            111                                                             179            139                                                             180            136                                                             181            125                                                             183            107                                                             185            115                                                             188            188                                                             189            133                                                             191            165                                                             193            226                                                             254            232                                                             287            170                                                             288            232                                                             297            229                                                             ______________________________________                                    

3. Antitoxidant activity:

Antitoxidant activity is determined according to the method of Stocks et al. (Clin, Sci. Mol. Med., 47: 215 (1974)). Rat cerebrum is added to ice-cooled 40 mM phosphate saline buffer solution (PBS) (pH 7.4, 4 ml buffer per 1 g cerebrum), homogenized and centrifuged (1000×g, 4° C., 10 min.) to obtain supernatant solution. The supernatant solution is diluted five-fold with the above ice-cooled PBS solution, and to a 0.9 ml aliquot thereof is added a sample containing a compound [1] (0.1 ml, final concentration 100 μM) dissolved in ethanol. The resultant mixture is incubated at 37° C. for 15 mins., 35% perchloric acid (0.2 ml) is added, and the mixture is then ice-cooled to stop the reaction and centrifuged (1300×g, 4° C., 10 min.). 0.5 ml thiobarbituric acid (5 g/lit. of 50% acetic acid) is added to the supernatant solution (1 ml), whereafter it is heated at 100° C. for 30 mins. and ice-cooled, so as to measure its absorbency at 532 nm. The amount of lipoperoxide thus-generated is expressed as an amount of malondialdehyde. The results are shown in Table 5, where it will be seen that the compounds [1] of the present invention inhibit lipoperoxide generation.

                  TABLE 5                                                          ______________________________________                                         Antioxidant Activity                                                                  Compound                                                                               Inhibition                                                             No.     %                                                               ______________________________________                                                115     44                                                                     119     41                                                                     129     53                                                                     132     53                                                                     133     51                                                                     134     49                                                                     142     48                                                                     143     53                                                                     150     45                                                                     154     51                                                                     158     44                                                                     160     41                                                                     161     76                                                                     162     47                                                                     165     70                                                                     168     59                                                                     175     49                                                                     176     88                                                                     177     73                                                                     178     67                                                                     180     69                                                                     183     41                                                                     185     63                                                                     256     66                                                                     258     87                                                                     260     62                                                                     264     79                                                                     267     68                                                                     268     77                                                                     269     70                                                                     270     93                                                                     272     83                                                                     273     77                                                                     274     77                                                                     275     80                                                                     276     67                                                                     277     70                                                                     278     87                                                                     279     73                                                                     280     67                                                                     281     77                                                                     282     87                                                                     283     53                                                                     295     55                                                                     305     61                                                                     306     54                                                                     307     50                                                                     308     57                                                                     309     71                                                                     310     79                                                                     311     89                                                                     312     93                                                                     313     89                                                                     314     75                                                                     315     82                                                                     316     86                                                                     317     68                                                                     318     82                                                                     319     89                                                                     320     86                                                                     321     75                                                                     322     79                                                                     323     75                                                                     324     64                                                                     325     92                                                                     326     88                                                                     327     92                                                                     328     72                                                                     329     88                                                                     330     92                                                                     331     88                                                                     332     80                                                                     334     56                                                                     335     80                                                                     336     96                                                                     337     88                                                                     338     80                                                                     339     72                                                                     340     92                                                                     378     52                                                                     385     67                                                                     386     50                                                                     387     77                                                                     467     61                                                                     472     53                                                                     473     58                                                                     478     59                                                                     479     53                                                                     487     72                                                                     488     84                                                                     489     78                                                                     490     75                                                              ______________________________________                                    

As explained hereinabove, a compound [1] of the present invention or its corresponding salt inhibits platelet aggregation, has vasodilating activity, and/or inhibits lipoperoxide generation, and is useful in pharmaceutical form for treating circulatory and metabolic disorders.

EXAMPLES

The following examples are illustrative of the present invention, but are not to be construed as limiting.

In the examples, the Rf value of silica-gel thin layer chromatography (TLC) is either specified by or measured using the following carrier and developing solvent:

Carrier: silica-gel, Kieselgel 60 F₂₅₄ (Merck)

Developer: chloroform-methanol (20:1)

Physical properties of the compounds [1] obtained in the following examples are shown in Table 27.

Example 1 1-(2-hydroxyethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine (compound 026)

2-Hydroxy-3,5,6-trimethylpyrazine (13.8 g, 0.1M) and 5N NaOH (100 ml, 0.5M) were added to t-butanol (200 ml). Ethylene chlorohydrin (40.3 g, 0.5M) was added thereto and the mixture was stirred at 60° C. for 2 hours. Water was added to the reaction mixture, which was then extracted 10 times with chloroform (100 ml), and the extract dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (Wako Pure Chem. Co., C-200) and eluted with chloroform-methanol (300:1) to obtain the product (14.4 g, yield: 79.1%).

Dihydrochloride: m.p.: 140°-144° C.

Examples 2-9 1-(2-substituted ethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine

Thionylchloride (0.86 ml, 12 mM) in chloroform (0.5 ml) was added dropwise under ice-cooling to the compound 026 (1.82 g, 10 mM) suspended in chloroform (5 ml) and stirred at room temperature for 3 hours to chlorinate. The reaction mixture was poured into dilute aqueous Na₂ CO₃, extracted three times with chloroform, and the extract dried with anhydrous sodium sulfate and concentrated in vacuo.

The obtained chlorinated compound was dissolved in benzene (60 ml), base (20 mM) and triethylamine (2.8 ml, 20 mM) were added thereto, and the mixture was refluxed. The reaction mixture was washed with dilute aqueous Na₂ CO₃ and the aqueous layer was extracted two times with benzene. The combined benzene layer, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. The residue was chromatographed on a silica-gel (80 g) column residue using an elution solvent of chloroform-methanol to obtain the compounds in Table 6.

Table 6 shows the identify of the base, the reflux time and the ratio of chloroform-methanol mixture used in each of the above examples.

Examples 10-11 1-(2-substituted thioethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine

Compound 026 (0.91 g, 5 mM) was chlorinated with thionylchloride according to the same method used in Examples 2-9. The thus-obtained chlorinated compound was dissolved in dimethylformamide (DMF, 10 ml), sodium mercaptan (5 mM) was added, and the mixture was stirred at room temperature for 2 days. DMF was driven off in vacuo. Dilute aqueous K₂ CO₃ solution was added to the residue, whereafter it was extracted with chloroform, dried by adding anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica-gel (C-200, 50 g) column eluted with benzene-ethyl acetate (5:1) to obtain the product in Table 7.

Table 7 shows the particular mercaptans used in the above examples.

Example 12 1,4-bis[2-(3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine-1-yl)ethyl]piperazine (compound 101)

Chloroform (3 ml) in solution with thionylchloride (4.3 ml, 60 mM) was added dropwise under ice-cooling to compound 026 (9.10 g, 50 mM) suspended in chloroform (15 ml). After stirring at room temperature for 3 hours, the reaction mixture was poured into dilute aqueous K₂ CO₃ and extracted with chloroform (200 ml). The chloroform layer was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in benzene (300 ml), piperazine (2.15 g) and triethylamine (0.8 ml, 50 mM) were added, and the mixture was refluxed for 3 hours. The reaction mixture was washed with dilute aqueous K₂ CO₃ and the aqueous layer was extracted with chloroform. The chloroform layer was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 180 g), and eluted with chloroform-methanol (100:1) to obtain compound 101 (7.60 g, yield: 73.2%).

Example 13 1-(2-piperazinoethyl)-3,5,6-trimethyl-1,2-dihydropyrazine (compound 642)

Piperazine (17.2 g, 0.2M) and triethylamine (28 ml, 0.2M) were used in the method of Example 12, the other conditions being preserved, to obtain compound 642 (5.52 g, yield: 44.2%) which displayed a lower Rf value relative to compound 101.

Example 14 1-(2-hydroxyethyl)-3-phenyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 109)

Ethylene chlorohydrin (20.2 g, 0.25M) was added to a solution of 2-hydroxy-3-phenyl-5,6-dimethyl-pyrazine (10.0 g, 50 mM) and 5N NaOH (50 ml) in t-butanol (150 ml), and stirred at 60° C. for 2.5 hours. Water was added to the reaction mixture, the mixture extracted with chloroform, and the extract dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 130 g) packed with chloroform and eluated with chloroform-methaol (100:1) to obtain compound 109 (8.73 g, yield: 71.5%).

Example 15 1-(2-chloroethyl)-3-phenyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 612)

Thionylchloride (0.42 ml, 6.0 mM) was added dropwise under ice-cooling to compound 109 (1.22 g, 50 mM) dissolved in chloroform (10 ml), and stirred at room temperature for 3 hours. Chloroform was added to the reaction mixture, whereafter the mixture was washed with dilute aqueous K₂ CO₃ and the resultant aqueous layer extracted with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g), and eluted with chloroform to obtain compound 612 (0.59 g, yield: 42.7%).

Examples 16-17 1-(2-substituted ethyl)-3-phenyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine

Base (5 mM) and triethylamine (0.70 ml, 5 mM) were added to compound 612 (0.66 g, 2.5 mM) dissolved in benzene (15 ml), and refluxed. The reaction mixture was washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted with benzene. The benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 65 g) and eluted with chloroform-methanol to obtain the compounds in Table 8.

Table 8 identifies the base, reflux time and the ratio of the chloroform-methanol mixture used in the above examples.

Example 18 1-(2-hydroxyethyl)-3-benzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 112)

Ethylene chlorohydrin (4.03 g, 50 mM) was added to a solution of 2-hydroxy-3-benzyl-5,6-dimethyl-pyrazine (2.14 g, 10 mM) and 5N NaOH (10 ml) in t-butanol (30 ml), and stirred at 60° C. for 2.5 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted three times with chloroform, the extract dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g) and eluted with chloroform-methanol (100:1) to obtain compound 112 (2.22 g, yield: 86.0%).

Example 19 1-(2-chloroethyl)-3-benzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 613)

Thionylchloride (0.42 ml, 6.0 mM) was added dropwise under ice-cooling to a compound 112 (1.29 g, 5 mM) dissolved in chloroform (6 ml), and stirred at room temperature for 5 hours. Chloroform (70 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃, the resulting aqueous layer being twice extracted with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g), packed with chloroform, and eluted with chloroform to obtain compound 613 (1.00 g, yield: 87.5%).

Examples 20-23 1-(2-substituted ethyl)-3-benzyl-5,6-dimethyl-2-oxo 1,2-dihydropyrazine

Base (6.0 mM) and triethylamine (0.84 ml, 6.0 mM) were added to compound 613 (0.83 g, 3.0 mM) dissolved in benzene (15 ml), and refluxed. The reaction mixture was washed with dilute aqueous K₂ CO₃, and the aqueous layer extracted with further benzene. The benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds of Table 9.

Table 9 identifies the base, reflux time and ratio of chloroform-methanol mixture used in the above examples.

Examples 24-28 1-(2-hydroxyethyl)-3-alkyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine

Aqueous 5N NaOH (10 ml, 50 mM), t-butanol (30 ml) and ethylene chlorohydrin (50 mM) were added to 2-hydroxy-3-alkyl-5,6-dimethyl-pyrazine (10 mM) and stirred at 60° C. Water was added to the reaction mixture, which mixture was then extracted three times with chloroform, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 120 g) and eluted with chloroform-methanol to obtain the compounds (hydroxy ethyl form) of Table 10.

Table 10 identifies the specific 2-hydroxy-3-alkyl-5,6-dimethyl-pyrazine, its amount used, reaction time in hours, and ratio of mixture of chloroform-methanol used in each of the above examples.

Examples 29-46 1-(2-substituted ethyl)-3-alkyl-5,6-trimethyl-2-oxo 1,2-dihydropyrazine

Thionylchloride (0.34 ml) was added dropwise under ice-cooling to the hydroxy ethyl form (4 mM) of the compounds obtained in Examples 24-28, and the reaction mixture was dissolved in chloroform (5 ml) and stirred at room temperature for one hour. Chloroform was added to the reaction mixture, which mixture was washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted twice with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30 ml), triethylamine (1.12 ml) and base (8 mM) were added to the residue and the resultant mixture was refluxed. Chloroform (100-120 ml) was added to the reaction mixture and washed with dilute aqueous K₂ CO₃. The aqueous layer was extracted twice with chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 60 g) and eluted with chloroform-methanol to obtain the compounds shown in Table 11.

Table 11 identifies the starting material (hydroxy ethyl form), base, reflux time and ratio of chloroform-methanol mixture used in the above examples.

Examples 47-49 1-(2-hydroxyethyl)-3-alkyl-5,6-dimethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline

Aqueous 5N NaOH (10 ml, 50 mM), t-butanol (30 ml) and ethylene chlorohydrin (50 mM) were added to 2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline (10 mM) and stirred at 60° C. Water was added to the reaction mixture, which mixture was then extracted with chloroform, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200) and eluted with chloroform-methanol to obtain the compounds (hydroxy ethyl form) of Table 12.

Table 12 identifies the specific 2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline (group R₁), its amount used, reaction time in hours, and ratio of the chloroform-methanol mixture used in the above examples.

Examples 50-62 1-(2-substituted ethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline

Thionylchloride (0.34 ml) was added dropwise under ice-cooling to the hydroxy ethyl form (4 mM) of the compounds obtained in Examples 47-49, dissolved in chloroform and stirred at room temperature for one hour. Chloroform was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted with chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30 ml), triethylamine (1.12 ml, 8 mM) and base (8 mM) were added to the reaction mixture, followed by refluxing. Chloroform (100 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted with chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 70 g) and eluted with chloroform-methanol to obtain the compounds shown in Table 13.

Table 13 identifies the starting material (hydroxy ethyl form), base, reflux time and ratio of chloroform-methanol mixture used in the above examples.

Examples 63-68 1-(2-hydroxyethyl)-3-alkyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine

Aqueous 5N NaOH (10 ml, 50 mM), t-butanol (30 ml) and ethylene chlorohydrin (50 mM) were added to 2-hydroxy-3-alkyl-5,6-diethyl-pyrazine (10 mM) and stirred at 60° C. Water was added to the reaction mixture, which mixture was then extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo.

The residue was charged on a silica-gel column (C-200) packed with chloroform, and eluted with chloroform-methanol to obtain the compounds in Table 14.

Table 14 identifies the specific 2-hydroxy-3-alkyl-5,6-diethyl-pyrazine (group R₁), its amount used, reaction time in hours, amount of silica-gel and ratio of chloroform-methanol mixture used in each of the above examples.

Examples 69-101 1-(2-substituted ethyl)-3-alkyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine

Thionylchloride (0.34 ml) was added dropwise under ice-cooling to the hydroxy ethyl form (4 mM) of the compounds obtained in Examples 63-68, dissolved in chloroform (5 ml) and stirred at room temperature for one hour. Chloroform was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted twice with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30 ml), triethylamine (1.12 ml, 8 mM) and base (8 mM) were added to the residue, followed by refluxing. Chloroform (100 ml) was added to the reaction mixture, and the mixture was washed with dilute aqueous K₂ CO₃. The resultant aqueous layer was extracted with additional chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 60 g) packed with chloroform, and eluted with chloroform-methanol to obtain the compounds shown in Table 15.

Table 15 identifies the starting material (hydroxy ethyl form), base, reflux time and ratio of chloroform-methanol mixture used in the above examples.

Example 102 1-(2-hydroxyethyl)-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 630)

Ethylene chlorohydrin (32.21 g, 0.4M) was added to a solution of 2-hydroxy-3-ethyl-5,6-dimethyl-pyrazine (12.16 g, 80 mM) and 5N NaOH (80 ml) in t-butanol (240 ml), and stirred at 60° C. for 3 hours. Dilute aqueous K₂ CO₃ was added to the reaction mixture, the mixture extracted with chloroform, and the resultant aqueous layer extracted twice with further chloroform. The combined chloroform layers were dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 250 g) packed with chloroform and eluted with chloroform-methanol form-methanol (from 200:1 to 50:1) to obtain compound 630 (12.31 g, yield: 78.5%).

Examples 103-110 1-(2-substituted ethyl)-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine

Thionylchloride (0.43 ml) was added dropwise under ice-cooling to compound (0.98 g, 5 mM) dissolved in chloroform (5 ml), and stirred at room temperature for one hour. Chloroform (50 ml) was added to the reaction mixture, the mixture then washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted twice with additional chloroform (50 ml). The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30 ml), triethylamine (1.40 ml) and base (10 mM) were added to the residue and refluxed. Chloroform (100 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃. The resultant aqueous layer was extracted twice with chloroform (50 ml). The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 70 g) packed with chloroform, and eluted with chloroform-methanol to obtain the compounds shown in Table 16.

Table 16 identifies the base, reflux time and ratio of chloroform-methanol mixture used in the above examples.

Example 111 1-(2-hydroxyethyl)-3-benzyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine (compound 640)

Ethylene chlorohydrin (20.15 g, 0.25M) was added to a solution of 2-hydroxy-3-benzyl-5,6-diethyl-pyrazine (12.10 g, 50 mM) and 5N NaOH (50 ml) in t-butanol (150 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo, water was added thereto and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 230 g) packed with chloroform and eluted with chloroform-methanol (100:1) to obtain compound 640 (12.31 g, yield: 58.7%).

Examples 112-122 1-(2-substituted ethyl)-3-benzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine

Thionylchloride (0.34 ml) was added dropwise under ice-cooling to compound 640 (1.15 g, 4.0 mM) dissolved in chloroform (5 ml) and stirred at room temperature for one hour. Chloroform (100 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted twice with additional chloroform (30 ml). The chloroform layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. Triethylamine (1.12 ml, 8 mM) and base (8 mM) were addd to the residue dissolved in benzene (30 ml), followed by refluxing. The reaction mixture was washed with dilute aqueous K₂ CO₃. The resultant aqueous layer was extracted twice with benzene. The benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 60 g) and eluted with chloroform-methanol to obtain the compounds shown in Table 17.

Table 17 identifies the base, reflux time and ratio of chloroform-methanol mixtures used in the above examples.

Example 123 1-(2-hydroxyethyl)-3-p-chlorobenzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 641)

Ethylene chlorohydrin (16.11 g, 0.20M) was added to a solution of 2-hydroxy-3-p-chlorobenzyl-5,6-dimethylpyrazine (11.06 g, 40 mM) in aqueous 5N NaOH (40 ml) and t-butanol (120 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo. Dilute aqueous K₂ CO₃ was added to the residue, the resulting mixture being extracted three times with chloroform, dried wit anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 300 g) packed with chloroform and eluted with chloroform-methanol (100:1) to obtain compound 641 (9.73 g, yield: 75.9%).

Example 124 1-(2-chloroethyl)-3-p-chlorobenzyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine (compound 647)

Thionylchloride (1.20 ml) was added dropwise to compound 641 (4.16 g, 13 mM) dissolved in chloroform (20 ml) under ice-cooling and stirred at room temperature for 1.5 hours. Dilute aqueous K₂ CO₃ was added to the reaction mixture, the resulting mixture being extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo to obtain compound 647 (4.27 q, yield: 96.9%).

Examples 125-129 1-(2-substituted ethyl)3-p-chlorobenzyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine

Base (6 mM) and triethylamine were added to chloroethyl compound 649 (1.023 g, 3 mM) dissolved in benzene (30 ml), and refluxed. The reaction mixture was poured into dilute aqueous K₂ CO₃, the resultant aqueous layer being washed and extracted with benzene. The benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charge don a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds of Table 18.

Table 18 identifies the base, reflux time and ratio of chloroform-methanol mixture used in the above examples.

Examples 130-138 1-(2-hydroxyethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline

Ethylene chlorohydrin (4.03 g, 50 mM) was added to a solution of 2-hydroxy-3-alkyl-5,6,7,8-tetrahydro quinoxaline (10 mM) in aqueous 5N NaOH (10 ml, 50 mM) and t-butanol (30 ml), and stirred at 60° C. for 4 hours. Water was added to the reaction mixture, which mixture was then extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200) packed with chloroform and eluted to obtain the compounds (hydroxy ethyl form) of Table 19.

The kind of 2-hydroxy-3-alkyl-5,6,7,8-tetrahydro quinoxaline (group R₁), its amount used, amount of silica gel used in column chromatography and kind of elution solvent are illustrated in Table 19.

Examples 139-214 1-(2-substituted ethyl)-3-alkyl-2-oxo-1,2,3,5,6,7,8-hexahydroquinoxaline

Thionylchloride (1.3 equivalent) was added dropwise under ice-cooling to the hydroxyl ethyl form (3-5 mM) of the compounds obtained in Examples 130-138, dissolved in chloroform (3-5 ml) and stirred at room temperature for one hour. Dilute aqueous K₂ CO₃ was added to the reaction mixture, which mixture was then extracted three times with chloroform (50 ml), dried with anhydrous sodium sulfate, and concentrated in vacuo. Benzene (30 ml), triethylamine (2 eq.) and base (2 eq.) were added to the residue, followed by refluxing. The reaction mixture was poured into dilute aqueous K₂ CO₃, then extracted several times with benzene. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 60 g) and eluted with chloroform-methanol (200:1) to obtain the compounds shown in Table 20.

The kind of starting material (hydroxy ethyl form), amount thereof used, base and reflux time are shown in Table 20.

Example 215 1-(2-piperazinyl ethyl)-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine

Thionylchloride (6.6 ml) was added dropwise under ice-cooling to compound 630 (13.72 g, 70 mM) dissolved in chloroform (70 ml), and stirred at room temperature for one hour. Dilute aqueous K₂ CO₃ was added to the reaction mixture, which was then extracted with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. Triethylamine (19.6 ml, 0.14M) and anhydrous piperazine (64.4 g, 0.75M) were added to the residue dissolved in benzene (420 ml), and refluxed for 3 hours. The reaction mixture was washed with dilute aqueous K₂ CO₃. The resultant aqueous layers was extracted with benzene. The benzene layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 375 g) packed with chloroform and eluted with chloroform-methanol (10:1) to obtain compound 454 (13.66 g, yield: 73.9%).

Examples 216-226 1-[2-(4'-arylpiperazinyl)ethyl]-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine

(a) Acid chloride method:

Triethylamine (0.84 ml, 6 mM) was added to compound 454 (0.81 g, 3 mM) dissolved in chloroform (10 ml), and acid chloride (3 mM) was added thereto under ice-cooling. Dilute aqueous K₂ CO₃ was added to the reaction mixture, which mixture was then extracted three times which chloroform. The combined chloroform layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 80 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 21.

(b) Mixed anhydride method:

Triethylamine (0.70 ml) was added to the carboxylic acid (5 mM) dissolved in tetrahydrofuran (10 ml). After pivaloyl chloride (0.61 g, 5 mM) was added dropwise thereto at -5° C. and stirred for 30 mins., a solution of compound 454 (1.06 g, 4 mM) in chloroform was added dropwise. Reaction was continued under gradually increasing temperature, up to room temperature. The reaction mixture was thereafter treated as in method (a) above, to obtain the products shown in Table 21.

Acylation method, acylating agent used, reaction time and ratio of chloroform-methanol mixture are shown in Table 21.

Example 227 1-(2-hydroxyethyl-3-benzyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 643)

Ethylene chlorohydrin (16.10 g, 0.2M) was added to a solution of 2-hydroxy-3-benzyl-5,6,7,8-tetrahydro quinoxaline (9.60 g, 40 mM) in dilute aqueous 5N NaOH (40 ml) and t-butanol (120 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo. The residue was extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 220 g) packed with chloroform, and eluted with chloroform-methanol (200:1) to obtain compound 643 (10.90 g, yield: 83.8%).

Example 228 1-(2-chloroethyl)-3-benzyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 644)

Thionylchloride (2.96 ml, 1.3 eq.) was added dropwise under ice-cooling to compound 643 (9.09 g, 32 mM) dissolved in chloroform (30 ml), and stirred at room temperature for 2 hours. Dilute aqueous K₂ CO₃ was added to the reaction mixture, which mixture was then extracted twice with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 100 g) packed with chloroform and eluted with chloroform to obtain a compound 644 (7.55 g, yield: 78.0%).

Examples 229-234 1-(2-substituted ethyl)-3-benzyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline

Base (7 mM) and triethylamine (0.98 ml) were added to compound 644 (1.05 g, 3.5 mM) dissolved in benzene (30 ml), and refluxed. The reaction mixture was washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer was extracted with benzene. The combined benzene layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 22.

The kind of base, reflux time and ratio of chloroform-methanol mixture are shown in Table 22.

Example 235 1-(2-hydroxyethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 645)

Ethylene chlorohydrin (9.0 g) was added to a solution of 2-hydroxy-3-(2-phenylethyl)-5,6,7,8-tetrahydro quinoxaline (5.59 g, 22 mM) in aqueous 5N NaOH and t-butanol (60 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo, water was added to the residue, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 170 g) packed with chloroform, and eluted with chloroform-methanol (200:1) to obtain compound 645 (6.73 g, yield: 90.9%).

Example 236 1-(2-chloroethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 647)

Thionylchloride (2.05 ml) was added dropwise under ice-cooling to compound 645 (6.49 g, 22.1 mM) dissolved in chloroform (25 ml), and stirred at room temperature for 2 hours. Dilute aqueous K₂ CO₃ was added to the reaction mixture, which mixture was then extracted twice with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo to obtain compound 647, which was used without further purification in the following reactions.

Examples 237-241 1-(2-substituted ethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline

Base (7 mM) and triethylamine (0.98 ml) were added to compound 647 (1.11 g, 3.5 mM) dissolved in benzene (30 ml), and refluxed. The reaction mixture was washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer was extracted with benzene. The combined benzene layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200), 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 23.

The kind of base, reflux time and ratio of chloroform-methanol mixture are shown in Table 23.

Example 242 1-(2-hydroxyethyl)-3-ethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 646)

Ethylene chlorohydrin (20.2 g, 0.25M) was added to a solution of 2-hydroxy-3-ethyl-5,6,7,8-tetrahydro quinoxaline (8.90 g, 50 mM) in dilute aqueous 5N NaOH (50 ml) and t-butanol (150 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo. Water was added to the residue, which residue was then extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 170 g) packed with chloroform, and eluted with chloroform-methanol (100:1) to obtain compound 646 (9.30 g, yield: 83.8%).

Examples 243-248 1-(2-substituted ethyl)-3-ethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline

Thionylchloride (0.47 ml) was added dropwise under ice-cooling to compound 646 (1.11 g, 5 mM) dissolved in chloroform (4 ml), and stirred at room temperature for one hour. Dilute aqueous K₂ CO₃ was added to the reaction mixture, which mixture was then extracted with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo.

Benzene (30 ml), triethylamine (1.4 ml) and base (10 mM) were added to the residue, followed by refluxing. The reaction mixture was poured into dilute aqueous K₂ CO₃ and extracted with benzene. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 24.

The kind of base, reflux time and ratio of chloroform-methanol mixture are shown in Table 24.

Example 249 1-(2-acetoxyethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine (compound 061)

Acetic anhydride (2 ml) was added under ice-cooling to compound 026 (0.91 g, 5 mM) dissolved in pyridine (10 ml), and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and dilute aqueous K₂ CO₃ was added thereto, the resultant mixture being extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (Florisil, 60 g) packed with benzene and eluted with benzene-ethyl acetate (5:1) to obtain compound 061 (0.58 g, yield: 51.8%).

Example 250 1-(2-phenylthioethyl)-3-propyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 615)

Thionylchloride (0.47 ml) was added dropwise under ice-cooling to compound 614 (1.18 g, 5 mM, hydroxy ethyl form) as obtained in Example 47 dissolved in chloroform (5 ml), and stirred at room temperature for one hour. Chloroform was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃ and extracted with chloroform. The combined chloroform layer was dried with anhydrous magnesium sulfate and concentrated in vacuo.

Sodium thiophenolate (0.66 g) was added to the residue dissolved in DMF (20 ml), and stirred at room temperature for 2 days. DMF was distilled off in vacuo, dilute aqueous K₂ CO₃ was added to the residue, and the resulting mixture was extracted with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo.

The residue was charged on a column of silica-gel (C-200, 50 g) and eluted with benzene-ethyl acetate (5:1) to obtain compound 615 (1.32 g, yield: 80.7%).

Comparative Example 1 2-hydroxy-3-ethyl-5,6,7,8-tetrahydroquinoxaline

1,2-cyclohexanedione (6.72 g, 60 mM) was added all at once to a methanol solution (100 ml) of α-aminobutylamide (5.1 g, 50 mM) at -30° C., and aqueous 12.5N NaOH (5 ml) was added dropwise thereto. The reaction mixture was stirred at -30° C. for 30 mins., whereafter the cooling was removed and the mixture was stirred at room temperature for 3 hours. Concentrated hydrochloric acid (6.25 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (5 g) was added after 10 mins., the methanol being distilled off in vacuo. The residue was extracted with chloroform, and the extract was washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product as colorless crystals (5.3 g, yield: 60%, m.p.: 152°-153° C.).

NMR (CDCl₃) δ (ppm): 1.25 (t, 3H, --CH₂ CH₃), 1.7-1.9 (m, 4H, 6-H₂, 7-H₂), 2.5-2.8 (m, 4H, 5-H₂, 8-H₂), 2.80 (q, 2H, --CH₂ CH₃), 13.06 (br. s, 1H, OH)

Mass (CI): 179 (M³⁰ +1)

Comparative Example 2 2-hydroxy-3-propyl-5,6,7,8-tetrahydroquinoxaline

1,2-cyclohexanedione (5.4 g, 48 mM) was added all at once to a methanol solution (80 ml) of norvalineamide hydrochloride (6.1 g, 40 mM) at -30° C., and aqueous 12.5N NaOH (8 ml) was added dropwise thereto. The reaction mixture was stirred at -30° C. for 30 mins., cooling was removed, and the mixture stirred to room temperature for 3 hours. Conc. hydrochloric aicd (10 ml) was added to the reaction mixture under ice-cooling, sodium bicarbonate (8 g) was added after 10 mins., the methanol then being distilled off in vacuo. The residue was extracted with chloroform, and the extract washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product as colorless crystals (3.8 g., yield: 50%, m.p.: 131°-133° C.).

NMR (CDCl₃) δ (ppm: 1.00 (t, 3H, --CH₂ CH₂ CH₃), 1.55-1.90 (m, 4H, 6-H, --CH₂ CH₂ CH₃, 6-H₂, 7-H₂), 2.67-2.83 (m, 6H, --CH₂ CH₂ CH₃, 5-H₂, 6-H₂), 13.09 (br. s, 1H, OH)

Mass (CI): 193 (M⁺ +1)

Comparative Examples 3-13 2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxazline

1,2-cyclohexanedione (6.72 g, 60 mM) was added all at once to a methanol solution (100 ml) of α-amino acidamide hydrochloride (50 mM) at -30° C., and aqueous 12N NaOH (10 ml) was added dropwise thereto. The reaction mixture was stirred for 30 mins., cooling was removed, and the mixture was stirred at room temperature for 5 hours. Conc. hydrochloric acid (12.5 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (10 g) was added after 10 mins., whereafter the methanol was distilled off in vacuo. The residue was extracted with chloroform, and the extract was washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product shown in Table 25.

The kind of product, yield (weight and %) and physical properties are shown in Table 25.

Comparative Example 14 2-hydroxy-3-benzyl-5,6,7,8-tetrahydroquinoxaline

A methanol (30 ml) solution of 1,2-cyclohexanedione (13.44 g, 0.12M) was added to phenylalanineamide hydrochloride (20.05 g, 0.1M) dissolved in methanol (200 ml) under cooling below -30° C., and aqueous 12.5N NaOH (20 ml) was added dropwise thereto. The reaction mixture was stirred under -30° C. for 30 mins., whereafter cooling was removed and the mixture was stirred at room temperature for 3 hours. Conc. hydrochloric acid (25 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (15 g) was added after 10 mins. stirring, the methanol then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, and the extract was washed with water, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product (19.7 g, yield: 82.1%).

NMR (CDCl₃, TMS) δ (ppm): 1.6-2.0 (m, 4H), 2.4-2.7 (m, 4H), 4.02 (s, 2H), 7.0-7.4 (m, 5H)

Mass (CI): 241 (M⁺ +1)

Comparative Example 15 2-hydroxy-3-(phenylethyl)-5,6,7,8-tetrahydroquinoxaline

A methanol (20 ml) solution of 1,2-cyclohexanedione (5.38 g) was added to a methanol suspension (100 ml) of α-amino-(3-phenyl)-butylamine hydrochloride (8.58 g, 40 mM) at below -30° C., and aqueous 12.5N NaOH (8 ml) was added dropwise thereto. The reaction mixture was stirred at below -30° C. for 30 mins., cooling was removed, and the mixture was stirred at room temperature for 6 hours. Conc. hydrochloric acid (8 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (6.0 g) was added after 10 mins. stirring, the methanol then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, whereafter the extract was washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product (6.79 g, yield: 66.8%).

NMR (CDCl₃, TMS) δ (ppm): 1.6-2.0 (m, 4H), 2.5-2.8 (m, 4H), 3.06 (s, 2H×2), 7.1-7.3 (s, 5H), 12.9 (br. s, 1H)

Mass (CI): 225 (M⁺ +1)

Comparative Examples 16-23 2-hydroxy-3-alkyl-5,6-diethylpyrazine

α-amino acidamide (0.20M) and 3,4-hexane (22.8 g, 020M) were added to triethylamine (200 ml), the mixture was stirred at room temperature for 30 mins. and refluxed for 15 hours. Triethylamine was distilled off in vacuo, and the residue was dissolved in chloroform and washed with dilute aqueous K₂ CO₃. The chloroform layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the products shown in Table 26.

Product, yield, (weight and %) and physical properties are shown in Table 26.

                                      TABLE 6                                      __________________________________________________________________________     1-(2-substituted ethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine                                       Starting                                                                            Heat Elution solvent                             Example                                                                             Product*                                                                            Base           Material*                                                                           time (hr)                                                                           ratio   Yield (g)                                                                           Yield (%)                      __________________________________________________________________________     2    018                                                                                  ##STR228##    026  1.75h                                                                               20:1    1.96 78.5                           3    019                                                                                  ##STR229##    026  4    40:1    1.61 64.1                           4    020                                                                                  ##STR230##    026  1.75 20:1    1.70 64.4                           5    021                                                                                  ##STR231##    026  2    10:1    2.25 76.5                           6    022  1-imidazole    026  2    50:1    1.45 62.4                           7    023                                                                                  ##STR232##    026  5    100:1   2.42 71.2                           8    024                                                                                  ##STR233##    026  5    100:1   3.34 86.5                           9    025                                                                                  ##STR234##    026  5    100:1   3.64 97.2                           __________________________________________________________________________      *Compound No.                                                            

                  TABLE 7                                                          ______________________________________                                         1-(2-substituted thioththyl)-                                                  3,5,6-trimethy-2-oxo-1,2-dihydropyrazine                                       Ex-                         Starting                                                                              Yield Yield                                 ample Product* Mercaptane   material*                                                                             (g)   (%)                                   ______________________________________                                         10    027      HS--Ph       026    1.06  77.4                                  11    028      1-methyl-5-  026    1.04  78.8                                                 mercaptotetrazole                                               ______________________________________                                          *Compound No.                                                            

                                      TABLE 8                                      __________________________________________________________________________     1-(2-substituted ethyl)-3-phenyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine                                 Starting                                                                            Heat Elution solvent                             Example                                                                             Product*                                                                            Base           material*                                                                           time (hr)                                                                           ratio   Yield (g)                                                                           Yield (%)                      __________________________________________________________________________     16   110                                                                                  ##STR235##    612  3    100:1   0.70 89.5                           17   111                                                                                  ##STR236##    612  3    100:1   0.99 91.0                           __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 9                                      __________________________________________________________________________     1-(2-substituted ethyl)-3-benzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine                                 Starting                                                                            Heat Elution solvent                             Example                                                                             Product*                                                                            Base           material*                                                                           time (hr)                                                                           ratio   Yield (g)                                                                           Yield (%)                      __________________________________________________________________________     20   113                                                                                  ##STR237##    613   3h  100:1   0.78 79.5                           21   114                                                                                  ##STR238##    613  2    100:1   1.07 85.5                           22   115                                                                                  ##STR239##    613  3    100:1   0.78 57.7                           23   116                                                                                  ##STR240##    613  2    100:1   0.96 71.0                           __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 10                                     __________________________________________________________________________     1-(2-hydroxyethyl)-3-alkyl-5,6-dimetyl-2-oxo-1,2-dihydropyrazine                                     Reaction                                                                            Elution                                             Example                                                                             Product*                                                                            Starting material (R.sub.1)                                                                time (hr)                                                                           solvent ratio                                                                         Yield (g)                                                                           Yield (%)                               __________________________________________________________________________     24   616  Pro 3.32 g (20 mM)                                                                          2 h 100:1  3.42 81.4                                    25   622  iso-Pro                                                                            4.50 g (27 mM)                                                                         2    100:1  4.32 76.2                                    26   624  Bu  2.70 g (15 mM)                                                                         2     50:1  3.31 98.5                                    27   617  iso-Bu                                                                             5.40 g (30 mM)                                                                         2     50:1  5.12 76.2                                    28   623  sec-Bu                                                                             4.50 g (25 mM)                                                                         2    100:1  4.74 84.6                                    __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 11                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-alkyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine                                Starting                                                                            Heat Elution                                       Example                                                                             Product*                                                                            Base         material*                                                                           time (hr)                                                                           solvent ratio                                                                         Yield (g)                                                                           Yield (%)                         __________________________________________________________________________     29   121                                                                                  ##STR241##  616  1.5h 100:1  0.94 67.4                              30   122                                                                                  ##STR242##  616  2    100:1  1.00 67.9                              31   123                                                                                  ##STR243##  617  2.5  150:1  0.72 61.4                              32   124                                                                                  ##STR244##  617  2    150:1  1.41 92.3                              33   125                                                                                  ##STR245##  617  1.5  150:1  1.58 94.8                              34   126                                                                                  ##STR246##  617  1.5  150:1  1.27 76.2                              35   619                                                                                  ##STR247##  617  1.5  150:1  1.16 72.5                              36   148                                                                                  ##STR248##  622  1.5  200:1  0.94 84.2                              37   149                                                                                  ##STR249##  622  1.5  200:1  1.42 96.5                              38   150                                                                                  ##STR250##  622  2    200:1  1.41 87.6                              39   151                                                                                  ##STR251##  622  2    150:1  1.21 78.4                              40   156                                                                                  ##STR252##  624  1.5  150:1  0.85 72.5                              41   157                                                                                  ##STR253##  624  1.5  150:1  1.03 67.4                              42   158                                                                                  ##STR254##  624  1.5  150:1  1.08 64.8                              43   152                                                                                  ##STR255##  623  1    150:1  0.49 41.8                              44   153                                                                                  ##STR256##  623  1.25 150:1  0.64 41.9                              45   154                                                                                  ##STR257##  623  1.25 150:1  1.05 63.0                              46   155                                                                                  ##STR258##  623  1.5  150:1  1.12 70.0                              __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 12                                     __________________________________________________________________________     1-(2-hydroxyethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydro quinoxaline                                   Reaction                                                                            Elution                                             Example                                                                             Product*                                                                            Starting material (R.sub.1)                                                                time (hr)                                                                           solvent ratio                                                                         Yield (g)                                                                           Yield (%)                               __________________________________________________________________________     47   614  Pro 6.26 g (32 mM)                                                                         1.25 h                                                                              50:1   7.15 94.7                                    48   621  Bu  5.15 g (25 mM)                                                                         2    50:1   6.15 98.4                                    49   618  iso-Bu                                                                             4.12 g (20 mM)                                                                         2    50:1   4.12 82.4                                    __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 13                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydro quinoxaline                               Starting                                                                            Heat Elution                                       Example                                                                             Product*                                                                            Base         material*                                                                           time (hr)                                                                           solvent ratio                                                                         Yield (g)                                                                           Yield (%)                         __________________________________________________________________________     50   118                                                                                  ##STR259##  614  3h   100:1  1.14 93.5                              51   119                                                                                  ##STR260##  614  3    100:1  1.21 95.8                              52   120                                                                                  ##STR261##  614  2.5  100:1  1.57 91.9                              53   117                                                                                  ##STR262##  614  2.5   50:1  0.70 62.2                              54   127                                                                                  ##STR263##  618  2.5  200:1  1.07 83.6                              55   128                                                                                  ##STR264##  618  1    200:1  1.58 96.8                              56   129                                                                                  ##STR265##  618  1    200:1  1.46 82.5                              57   141                                                                                  ##STR266##  621  1    200:1  0.76 59.6                              58   142                                                                                  ##STR267##  621  1    200:1  0.95 58.2                              59   143                                                                                  ##STR268##  621  2    200:1  1.49 84.2                              60   144                                                                                  ##STR269##  621  1    200:1  0.86 67.8                              61   145                                                                                  ##STR270##  621  2     50:1  0.92 63.5                              62   146                                                                                  ##STR271##  621  1.25 200:1  1.15 67.5                              __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 14                                     __________________________________________________________________________     1-(2-hydroxy ethyl )-3-alkyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine                                    Reaction                                                                            Elution                                            Example                                                                             Product*                                                                            Starting material (R.sub.1)                                                                 time (hr)                                                                           solvent ratio                                                                         Yield (g)                                                                           Yield (%)                              __________________________________________________________________________     63   620  Pro  7.76 g (40 mM)                                                                         5.5 h                                                                                50:1  6.89 73.3                                   64   625  iso-Pro                                                                             9.70 g (50 mM)                                                                         5.5  100:1  8.70 73.1                                   65   628  Bu  10.40 g (50 mM)                                                                         3    100:1  8.53 68.2                                   66   626  iso-Bu                                                                              5.20 g (25 mM)                                                                         3    100:1  5.08 81.3                                   67   627  sec-Bu                                                                             10.40 g (50 mM)                                                                         3    100:1  9.94 79.5                                   68   629  Et   4.50 g (25 mM)                                                                         2    100:1  4.38 78.2                                   __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 15                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-alkyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine                                     Starting                                                                            Heat Elution Sol-                              Example                                                                             Product*                                                                            Base             material*                                                                           time (hr)                                                                           vent ratio                                                                            Yield (g)                                                                           Yield (%)                     __________________________________________________________________________     69   130                                                                                  ##STR272##      620  3 h  100:1  0.77 62.7                          70   131                                                                                  ##STR273##      620  1.5  200:1  1.05 66.3                          71   132                                                                                  ##STR274##      620  1.25 200:1  0.90 52.1                          72   133                                                                                  ##STR275##      620  1.5  200:1  1.02 59.0                          73   134                                                                                  ##STR276##      620  1.25 200:1  0.63 36.5                          74   159                                                                                  ##STR277##      625  1.25 200:1  0.65 52.9                          75   160                                                                                  ##STR278##      625  1.25 200:1  0.74 46.8                          76   161                                                                                  ##STR279##      625  1.25 200:1  0.99 57.5                          77   162                                                                                  ##STR280##      625  1.25 200:1  0.55 33.2                          78   163                                                                                  ##STR281##      625  1.25 200:1  0.55 45.1                          79   164                                                                                  ##STR282##      625  1.25  50:1  0.47 33.6                          80   165                                                                                  ##STR283##      625  1.25 200:1  0.77 44.7                          81   166                                                                                  ##STR284##      626  1.25 200:1  1.20 70.1                          82   167                                                                                  ##STR285##      626  1.25 200:1  0.70 54.5                          83   168                                                                                  ##STR286##      626  1.25 200:1  1.17 65.6                          84   170                                                                                  ##STR287##      626  1.25 200:1  1.31 79.9                          85   171                                                                                  ##STR288##      627  1.25 200:1  0.33 25.9                          86   172                                                                                  ##STR289##      627  2     50:1  0.30 20.6                          87   173                                                                                  ##STR290##      627  1    200:1  0.68 53.0                          88   174                                                                                  ##STR291##      627  1    200:1  0.46 28.0                          89   175                                                                                  ##STR292##      627  1.25 200:1  0.39 22.8                          90   176                                                                                  ##STR293##      627  1    200:1  0.78 43.6                          91   177                                                                                  ##STR294##      627  1.25 200:1  0.52 29.1                          92   178                                                                                  ##STR295##      628  1.25 200:1  1.08 60.8                          93   179                                                                                  ##STR296##      628  1.25 200:1  0.92 56.1                          94   180                                                                                  ##STR297##      628  1.25 200:1  1.54 86.7                          95   181                                                                                  ##STR298##      628  1    200:1  0.90 70.5                          96   182                                                                                  ##STR299##      628  1.25 200:1  0.98 76.3                          97   183                                                                                  ##STR300##      628  1.25 200:1  1.28 74.8                          98   185                                                                                  ##STR301##      628  1.25 200:1  0.78 43.9                          99   187                                                                                  ##STR302##      629  2    200:1  0.86 77.6                          100  188                                                                                  ##STR303##      629  1.25 100:1  0.80 48.1                          101  189                                                                                  ##STR304##      629  1.25 100:1  0.79 51.7                          __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 16                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine                                     Starting                                                                            Heat Elution                                  Example                                                                             Product*                                                                            Base              material*                                                                           time (hr)                                                                           solvent ratio                                                                         Yield (g)                                                                           Yield                        __________________________________________________________________________                                                       (%)                          103  190                                                                                  ##STR305##       630  2    200:1  1.03 77.7                         104  191                                                                                  ##STR306##       630  2    200:1  1.54 79.3                         105  192                                                                                  ##STR307##       630  1.5  200:1  1.23 66.1                         106  193                                                                                  ##STR308##       630  2    200:1  1.70 88.5                         107  287                                                                                  ##STR309##       630  1    200:1  1.37 77.4                         108  288                                                                                  ##STR310##       630  1    200:1  1.42 70.6                         109  289                                                                                  ##STR311##       630  1    200:1  1.05 54.4                         110  290                                                                                  ##STR312##       630  1.5  200:1  1.39 69.7                         __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 17                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-benzyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine                                    Starting                                                                            Heat Elution solvent                           Example                                                                             Product*                                                                            Base             material*                                                                           time (hr)                                                                           ratio   Yield (g)                                                                           Yield                        __________________________________________________________________________                                                       (%)                          112  291                                                                                  ##STR313##      640   4h  100:1   1.15 81.0                         113  292                                                                                  ##STR314##      640  1    100:1   1.15 81.4                         114  293                                                                                  ##STR315##      640  3    100:1   1.11 62.5                         115  294                                                                                  ##STR316##      640  2    100:1   1.60 83.6                         116  295                                                                                  ##STR317##      640    2.5                                                                               100:1   0.95 46.3                         117  296                                                                                  ##STR318##      640  4    100:1   1.45 78.5                         118  297                                                                                  ##STR319##      640    2.5                                                                               100:1   0.99 52.2                         119  374                                                                                  ##STR320##      640  1    200:1   1.21 70.5                         120  375                                                                                  ##STR321##      640  1    200:1   0.99 67.4                         121  378                                                                                  ##STR322##      640  1    100:1   1.57 80.3                         122  380                                                                                  ##STR323##      640  2    200:1   0.73 42.4                         __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 18                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-p-chlorobenzyl-5,6-diethyl-2-oxo-1,2-dihydropyra     zine                                                                                                      Starting                                                                            Heat Elution solvent                           Example                                                                             Product*                                                                            Base             material*                                                                           time (hr)                                                                           ratio   Yield (g)                                                                           Yield                        __________________________________________________________________________                                                       (%)                          125  384                                                                                  ##STR324##      641  2    100:1   0.89 76.2                         126  467                                                                                  ##STR325##      641  2    100:1   1.10 76.6                         127  385                                                                                  ##STR326##      641  2    100:1   1.23 79.9                         128  386                                                                                  ##STR327##      641  2    100:1   1.15 75.4                         129  387                                                                                  ##STR328##      641  2    100:1   1.03 56.2                         __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 19                                     __________________________________________________________________________     1-(2-hydroxyethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydroquinozaline              Example                                                                             Product*                                                                            Starting material (R.sub.1)                                                               silica-gel                                                                          Elution solvent  Yield (g)                                                                           Yield (%)                      __________________________________________________________________________     130  631  --(CH.sub.2).sub.4 CH.sub.3                                                           30 mM                                                                              150 g                                                                               chloroform-methanol                                                                       (200:1)                                                                              6.44 81.3                           131  632  --(CH.sub.2).sub.5 CH.sub.3                                                           20 mM                                                                              100 g                                                                               chloroform-methanol                                                                       (200:1)                                                                              4.66 83.8                           132  633  --(CH.sub.2).sub.6 CH.sub.3                                                           30 mM                                                                              150 g                                                                               chloroform-methanol                                                                       (200:1)                                                                              8.39 95.8                           133  634  --(CH.sub.2).sub.7 CH.sub.3                                                           28 mM                                                                              150 g                                                                               chloroform-methanol                                                                       (200:1)                                                                              7.60 89.2                           134  635  --(CH.sub.2).sub.8 CH.sub.3                                                           40 mM                                                                              200 g                                                                               chloroform-methanol                                                                       (200:1)                                                                              11.00                                                                               85.9                           135  636  --(CH.sub.2).sub.9 CH.sub.3                                                           30 mM                                                                              150 g                                                                               chloroform-methanol                                                                       (200:1)                                                                              8.42 84.0                           136  637  --(CH.sub.2).sub.11 CH.sub.3                                                          20 mM                                                                              100 g                                                                               benzene-ethyl acetate                                                                     (5:1 → 3:1)                                                                   6.06 84.2                           137  638  --(CH.sub.2).sub.13 CH.sub.3                                                          15 mM                                                                              100 g                                                                               benzene-ethyl acetate                                                                     (5:1) 3.86 66.2                           138  639  --(CH.sub.2).sub.15 CH.sub.3                                                          20 mM                                                                              100 g                                                                               benzene-ethylacetate                                                                      (5:1 → 3:1)                                                                   5.92 70.8                           __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 20                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydro quinoxaline                                              Heat                                     Example                                                                             Product*                                                                            Starting material*                                                                       Base              time (hr)                                                                           Yield (g)                                                                           Yield (%)                      __________________________________________________________________________     139  250  631 1.06 g (4 mM)                                                                         ##STR329##       1.5 h                                                                               1.59 87.1                           140  251  631 1.06 g (4 mM)                                                                         ##STR330##       2    1.65 93.8                           141  252  631 1.32 g (5 mM)                                                                         ##STR331##       1.5  1.05 63.1                           142  253  631 1.06 g (4 mM)                                                                         ##STR332##       2    1.01 65.1                           143  254  631 1.06 g (4 mM)                                                                         ##STR333##       1.5  1.35 74.7                           144  255  632 1.25 g (4.5 mM)                                                                       ##STR334##       2    1.34 85.8                           145  256  632 0.95 g (3.5 mM)                                                                       ##STR335##       2    0.88 53.4                           146  257  632 0.95 g (3.5 mM)                                                                       ##STR336##       2    1.50 89.1                           147  258  632 1.12 g (4 mM)                                                                         ##STR337##       2    1.44 76.9                           148  305  632 1.12 g (4 mM)                                                                         ##STR338##       2    1.38 81.7                           149  306  632 1.12 g (4 mM)                                                                         ##STR339##       2    1.32 75.7                           150  307  632 1.12 g (4 mM)                                                                         ##STR340##       2    1.49 83.9                           151  308  632 1.12 g (4 mM)                                                                         ##STR341##       2    1.73 92.8                           152  309  632 1.12 g (4 mM)                                                                         ##STR342##       2.5  1.38 75.6                           153  310  632 1.12 g (4 mM)                                                                         ##STR343##       2.5  1.43 79.1                           154  311  632 1.12 g (4 mM)                                                                         ##STR344##       2.5  1.44 72.7                           155  312  632 1.12 g (4 mM)                                                                         ##STR345##       2    1.49 76.9                           156  313  632 1.12 g (4 mM)                                                                         ##STR346##       2    0.81 42.2                           157  259  633 1.17 g (4 mM)                                                                         ##STR347##       2    0.94 65.1                           158  260  633 1.17 g (4 mM)                                                                         ##STR348##       2    1.03 53.4                           159  261  633 1.17 g (4 mM)                                                                         ##STR349##       2    1.50 75.8                           160  262  633 1.17 g (4 mM)                                                                         ##STR350##       2    1.28 68.4                           161  263  633 1.17 g (4 mM)                                                                         ##STR351##       2    0.85 51.1                           162  264  633 1.17 g (4 mM)                                                                         ##STR352##       2    1.42 71.4                           163  314  633 1.17 g (4 mM)                                                                         ##STR353##       2    1.50 83.3                           164  315  633 1.17 g (4 mM)                                                                         ##STR354##       2    0.44 25.2                           165  316  633 1.17 g (4 mM)                                                                         ##STR355##       2    1.70 93.3                           166  317  633 1.17 g (4 mM)                                                                         ##STR356##       2    1.30 69.1                           167  318  633 1.17 g (4 mM)                                                                         ##STR357##       2.5  1.11 57.6                           168  319  633 1.17 g (4 mM)                                                                         ##STR358##       2    1.01 51.1                           169  320  633 1.17 g (4 mM)                                                                         ##STR359##       1.5  1.29 63.4                           170  265  634 1.23 g (4 mM)                                                                         ##STR360##       2    1.01 67.3                           171  266  634 0.92 g (3 mM)                                                                         ##STR361##       2    1.49 99.6                           172  267  634 0.92 g (3 mM)                                                                         ##STR362##       2    1.24 83.7                           173  268  634 0.92 g (3 mM)                                                                         ##STR363##       2    1.40 91.7                           174  269  634 0.92 g (3 mM)                                                                         ##STR364##       2    1.27 87.8                           175  270  634 1.23 g (4 mM)                                                                         ##STR365##       2    1.18 59.5                           176  321  634 1.23 g (4 mM)                                                                         ##STR366##       2    1.79 96.4                           177  322  634 1.23 g (4 mM)                                                                         ##STR367##       2    1.58 87.8                           178  323  634 1.23 g (4 mM)                                                                         ##STR368##       3    1.90 99.0                           179  324  634 1.23 g (4 mM)                                                                         ##STR369##       2    1.54 79.5                           180  325  634 1.23 g (4 mM)                                                                         ##STR370##       2    1.45 69.3                           181  326  634 1.23 g (4 mM)                                                                         ##STR371##       2    1.33 65.5                           182  327  634 1.23 g (4 mM)                                                                         ##STR372##       2    1.41 68.8                           183  271  635 1.28 g (4 mM)                                                                         ##STR373##       2    1.03 66.2                           184  272  635 0.96 g (3 mM)                                                                         ##STR374##       2    1.15 74.8                           185  273  635 0.96 g (3 mM)                                                                         ##STR375##       2    1.25 84.0                           186  274  635 0.96 g (3 mM)                                                                         ##STR376##       2    1.15 73.3                           187  275  635 0.96 g (3 mM)                                                                         ##STR377##       2    0.72 47.2                           188  328  635 0.96 g (3 mM)                                                                         ##STR378##       2    1.30 90.7                           189  329  635 0.96 g (3 mM)                                                                         ##STR379##       2    0.87 55.1                           190  330  635 0.96 g (3 mM)                                                                         ##STR380##       2.5  1.08 67.0                           191  331  635 0.96 g (3 mM)                                                                         ##STR381##       2    0.61 39.9                           192  332  635 0.96 g (3 mM)                                                                         ##STR382##       2    1.04 66.4                           193  334  636 1.01 g (3 mM)                                                                         ##STR383##       2    0.96 79.4                           194  335  636 1.01 g (3 mM)                                                                         ##STR384##       2    1.28 86.6                           195  336  636 1.01 g (3 mM)                                                                         ##STR385##       2    0.91 63.5                           196  337  636 1.01 g (3 mM)                                                                         ##STR386##       2.5  1.38 88.1                           197  338  636 1.01 g (3 mM)                                                                         ##STR387##       2    1.32 83.6                           198  339  636 1.01 g (3 mM)                                                                         ##STR388##       3    1.48 89.5                           199  340  636 1.01 g (3 mM)                                                                         ##STR389##       2    1.24                                200  276  637 1.09 g (3 mM)                                                                         ##STR390##       2    1.16 89.5                           201  277  637 1.09 g (3 mM)                                                                         ##STR391##       2    1.27 76.3                           202  278  637 1.09 g (3 mM)                                                                         ##STR392##       2    0.60 36.2                           203  279  637 1.09 g (3 mM)                                                                         ##STR393##       2    1.35 79.6                           204  280  638 1.17 g (3 mM)                                                                         ##STR394##       2    0.91 66.1                           205  281  638 1.17 g (3 mM)                                                                         ##STR395##       2    1.21 69.8                           206  282  638 1.17 g (3 mM)                                                                         ##STR396##       2    0.97 55.7                           207  487  638 1.17 g (3 mM)                                                                         ##STR397##       2    1.43 87.0                           208  488  638 1.17 g (3 mM)                                                                         ##STR398##       3    0.89 48.9                           209  489  638 1.17 g (3 mM)                                                                         ##STR399##       3    0.92 51.4                           210  490  638 1.17 g (3 mM)                                                                         ##STR400##       2.5  0.98 55.2                           211  283  639 1.26 g (3 mM)                                                                         ##STR401##       2    1.22 83.5                           212  284  639 1.26 g (3 mM)                                                                         ##STR402##       2    1.52 83.0                           213  285  639 1.26 g (3 mM)                                                                         ##STR403##       2    1.77 95.0                           214  286  639 1.26 g (3 mM)                                                                         ##STR404##       2    1.76 93.9                           __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 21                                     __________________________________________________________________________     1-[ 2-(4'-acylpiperadinyl)ethyl]-3-5,6-dimethyl-2-oxo-1,2-dihydropyrazine                Acylation            Reaction                                                                            Elution                                    Example                                                                             Product*                                                                            Method  Acylating agent                                                                             time solvent ratio                                                                         Yield (g)                                                                           Yield (5)                      __________________________________________________________________________     216  455  acid chloride                                                                          ClCO--CH.sub.2 Ph                                                                            1 h 100:1  0.93 81.2                           217  457  acid anhydride                                                                         2-thienylchloride                                                                           4    100:1  1.35 87.0                           218  459  acid anhydride                                                                         HOOC--CH.sub.2 Ph--NO.sub.2 (p)                                                             5    200:1  0.98 57.4                           219  465  acid chloride                                                                          CISO.sub.2 --Ph--Cl (p)                                                                     1    200:1  1.23 93.5                           220  456  acid anhydride                                                                         HOOC--Ph--Cl (p)                                                                            2    100:1  1.49 92.5                           221  458  acid anhydride                                                                         HOOC--Ph--NO.sub.2 (p)                                                                      2    100:1  1.59 96.2                           222  460  acid chloride                                                                          HOOC--Ph--OMe (p)                                                                           1    100:1  1.07 89.6                           223  461  acid anhydride                                                                         HOOC--Ph--OMe.sub.2 (2,3)                                                                   2    100:1  1.56 91.1                           224  462  acid anhydride                                                                         HOOC--Ph--OMe.sub.2 (2,4)                                                                   2    200:1  1.51 88.2                           225  463  acid anhydride                                                                         HOOC--Ph--OMe.sub.2 (3,4)                                                                   4    100:1  1.55 90.5                           226  464  acid anhydride                                                                         HOOC--Ph--OMe.sub.3 (3,4,5)                                                                 3    100:1  1.40 99.0                           __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 22                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-benzyl-2-oxo-1,2,5,6,7,8-hexahydro quinoxaline                                   Starting                                                                            Heat Elution solvent                          Compound                                                                             Product*                                                                            Base             material*                                                                           time (hr)                                                                           ratio   Yield (g)                                                                           Yield                       __________________________________________________________________________                                                        (%)                         229   470                                                                                  ##STR405##      643   3h  100:1   0.67 52.6                        230   471                                                                                  ##STR406##      643  3    100:1   1.01 62.3                        231   472                                                                                  ##STR407##      643  3    200:1   0.82 54.7                        232   473                                                                                  ##STR408##      643  3    200:1   1.10 66.0                        233   474                                                                                  ##STR409##      643    2.5                                                                               100:1   0.93 56.3                        234   475                                                                                  ##STR410##      643    2.75                                                                              100:1   1.15 71.4                        __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 23                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydro          quinoxaline                                                                                               Starting                                                                            Heat Elution solvent                           Example                                                                             Product*                                                                            Base             material*                                                                           time (hr)                                                                           ratio   Yield (g)                                                                           Yield                        __________________________________________________________________________                                                       (%)                          237  476                                                                                  ##STR411##      645   2h  100:1   1.07 83.3                         238  477                                                                                  ##STR412##      645  2    100:1   1.35 84.6                         239  478                                                                                  ##STR413##      645  2    200:1   1.01 65.2                         240  479                                                                                  ##STR414##      645    2.5                                                                               100:1   1.41 82.0                         241  480                                                                                  ##STR415##      645    2.5                                                                               100:1   0.98 57.6                         __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 24                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydro          quinoxaline                                                                                                Starting                                                                            Heat Elution                                  Example                                                                             Product*                                                                            Base              material*                                                                           time (hr)                                                                           solvent ratio                                                                         Yield (g)                                                                           Yield                        __________________________________________________________________________                                                       (%)                          243  481                                                                                  ##STR416##       646  2.5 h                                                                               100:1  0.98 62.6                         244  482                                                                                  ##STR417##       646  2.5  100:1  1.54 74.3                         245  483                                                                                  ##STR418##       646  2    100:1  1.67 87.9                         246  484                                                                                  ##STR419##       646  2.5  200:1  1.29 70.5                         247  485                                                                                  ##STR420##       646  2    100:1  1.25 58.3                         248  486                                                                                  ##STR421##       646  3    100:1  1.78 86.8                         __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 25                                     __________________________________________________________________________     2-hydroxy-3-alkyl-5,6,7,8-tetrahydro quinoxaline                                ##STR422##                                                                    Comp.       Yield                                                                              Yield                                                          Exa.                                                                               Product (R.sub.1)                                                                      (g) (%) NMR (CDCl.sub.3) δ (ppm)                                                                           Mass                             __________________________________________________________________________     3   Bu      7.49                                                                               73.0                                                                               0.94 (t, 3H,butyl 4-CH.sub.3), 1.24˜2.00 (m,                             butyl 2-CH.sub.2,         207 (M.sup.+  + 1)                                   3-CH.sub.2, quinoxaline 6-H.sub.2, 7-H.sub.2),                                 2.55˜2.85 (m, 6H, butyl                                                  1-CH.sub.2, quinoxaline 5-H.sub.2, 8-H.sub.2), 12.99                           (br. s, 1H, OH)                                            4   iso-Bu  6.58                                                                               64.0                                                                               0.96 (d, 6H, isobutyl 2 × CH.sub.3),                                     1.6˜2.0 (m, 4H, 6-H.sub.2, 7-                                                                      207 (M.sup.+  + 1)                                   H.sub.2), 2.0˜2.4 (isobutyl CH), 2.5˜2.8                           (m, 6H, 5-H.sub.2, 8-                                                          H.sub.2)                                                   5   (CH.sub.2).sub.4 CH.sub.3                                                              9.03                                                                               82.0                                                                               0.90 (t, 3H, J ≈ 6.3), 1.2˜1.5 (m, 4H),                          1.5˜1.9 (m,         221 (M.sup.+  + 1)                                   6H), 2.5˜2.9 (m, 6H)                                                                               164                              6   (CH.sub.2).sub.5 CH.sub.3                                                              7.81                                                                               66.7                                                                               0.88 (t, 3H, J ≈ 7.9), 1.1˜1.5 (m, 6H),                          1.5˜2.0 (m,         235 (M.sup.+  + 1)                                   6H), 2.4˜2.9 (m, 6H)                                 7   (CH.sub.2).sub.5 CH.sub.3                                                              9.33                                                                               75.0                                                                               0.88 (t, 3H, J ≈ 7.4), 1.1˜1.5 (m, 8H),                          1.5˜2.0 (m,         249 (M.sup.+  + 1)                                   6H), 2.5˜2.9 (m, 6H)                                 8   (CH.sub.2).sub.7 CH.sub.3                                                              11.67                                                                              89.1                                                                               0.88 (t, 3H, J ≈ 7.5), 1.1˜1.5 (m,                               10H), 1.5˜2.0 (m,   263 (M.sup.+  + 1)                                   6H), 2.5˜2.9 (m, 6H)                                 9   (CH.sub.2).sub.8 CH.sub.3                                                              12.73                                                                              92.2                                                                               0.88 (t, 3H, J ≈  6.2), 1.1˜1.5 (m,                              12H), 1.5˜2.0 (m,   277 (M.sup.+  + 1)                                   6H), 2.5˜2.8 (m, 6H)                                                                               164                              10  (CH.sub.2).sub.9 CH.sub.3                                                              10.46                                                                              72.4                                                                               0.88 (t, 3H, J ≈ 6.0), 1.2˜2.0 (m,                               20H), 2.5˜2.9 (m,   291 (M.sup.+  + 1)                                   6H), 12.7 (br. s, 1H)                                      11  (CH.sub.2).sub.11 CH.sub.3                                                             14.00                                                                              88.1                                                                               0.88 (t, 3H, J ≈ 6), 1.1˜1.9 (m, 24H),                           2.4˜2.8 (m, 6H)     319 (M.sup.+  + 1)                                                             164                              12  (CH.sub.2).sub.13 CH.sub.3                                                             16.58                                                                              95.8                                                                               0.88 (t, 3H, J ≈ 6), 1.1˜1.9 (m, 28H),                           2.4˜2.8 (m, 6H)     347 (M.sup.+  + 1)                                                             164                              13  (CH.sub.2).sub.15 CH.sub.3                                                             18.55                                                                              99.2                                                                               0.88 (t, 3H, J ≈ 6), 1.1˜1.9 (m, 32H),                           2.5˜2.8 (m, 6H)     375 (M.sup.+  + 1)                                                             164                              __________________________________________________________________________

                                      TABLE 26                                     __________________________________________________________________________     2-hydroxy-3-alkyl-5,6-diethylpyrazine                                           ##STR423##                                                                    Comp.      Yield                                                                              Yield                                                           Exa.                                                                               Product (R.sub.1)                                                                     (g) (%) NMR (CDCl.sub.3) δ (ppm)                                                                           Mass                              __________________________________________________________________________     16  Et     14.4                                                                               40  1.1˜1.4 (m, 9H), 2.3˜3.0 (m, 6H), 13.2                             (br. s, 1H)               167                               17  Pro    16.5                                                                               43  1.00 (t, 3H), 1.19 (t, 3H), 1.28 (t, 3H),                                      1.5˜1.9 (m,         181                                                  2H), 2.47 (q, 2H), 2.54 (q, 2H), 2.76 (q, 2H), 13.1                            (br. s, 1H)                                                 18  iso-Pro                                                                               18.2                                                                               47  1.0˜1.4 (m, 12H), 2.56 (q, 2H), 2.58 (q, 2H),                            3.40                      195                                                  (sept, 1H), 12.9 (br. s, 1H)                                19  Bu     17.5                                                                               42  0.95 (t, 3H), 1.19 (t, 3H), 1.27 (t, 3H),                                      1.2˜1.9 (m,         209                                                  4H), 2.57 (q, 2H × 2), 2.73 (t, 3H), 12.9 (br.                           s, 1H)                                                      20  iso-Bu 16.5                                                                               40  0.96 (t, 3H), 1.19 (t, 3H), 1.28 (t, 3H),                                      1.9˜2.4 (m,         209                                                  H), 2.41 (q, 2H), 2.58 (q, 2H), 2.66 (d, 2H), 13.0                             (br. s, 1H)                                                 21  sec-Bu 17.5                                                                               42  0.88 (t, 3H × 2), 1.0˜1.4 (m, 9H),                                 1.4˜2.0 (m, 2H),    209                                                  2.46 (q, 2H), 2.57 (q, 2H), 12.8 (br. s, 1H)                22  CH.sub.2 Ph                                                                           27.9                                                                               57.6                                                                               1.19 (t, 3H, J ≈ 7.6), 1.23 (t, 3H, J                                  ≈ 7.6), 2.50 (q, 2H,                                                                             243                                                  J ≈ 7.6), 2.53 (q, 2H, J ≈ 7.6), 4.07                          (s, 2H), 7.0˜7.4                                                         (m, 5H), 13.2 (br. s, 1H)                                   23  CH.sub.2 PhCl                                                                         27.4                                                                               49.6                                                                               1.19 (t, 3H, J ≈ 7.7), 1.23 (t, 3H, J                                  ≈ 7.7), 2.53 (q, 2H,                                                                             279                                   (p)            J ≈ 7.7), 2.57 (q, 2H, J ≈ 7.7), 4.03                          (s, 2H), 7.0˜7.4    277                                                  (m, 4H), 13.3 (br. s, 1H)                                   __________________________________________________________________________

                                      TABLE 27                                     __________________________________________________________________________     Compound Nos.                                                                          NMR (CDCl.sub.3, TMS) δ         Mass   TLC                       __________________________________________________________________________     018     1.3-1.8(6H,m), 2.30(3H,s), 2.38(3H,s), 2.41(3H,s), 2.5-2.8(6H,m),              4.1-4.3(2H,m)                         250(M.sup.+ + 1)                                                                      0.25                      019     2.31(3H,s), 2.34(3H,s), 2.41(3H,s), 2.5-2.7(6H,m), 3.6-3.8(4H,m),              4.0-4.2(2H,m)                         252(M.sup.+ + 1)                                                                      0.31                      020     2.29(3Hx2,s), 2.34(3H,s), 2.41(3H,s), 2.3-2.9(10H,m),                          4.0-4.2(2H,m)                         265(M.sup.+ + 1)                                                                      0.10                      021     2.30(3H,s), 2.34(3H,s), 2.41(3H,s), 2.4-2.7(12H,m), 2.92(1H,s),                2.63(2H,t,J≈                  295(M.sup.+ + 1)                                                                      0.08                              5.4), 4.0-4.2(2H,m)                                                    022     1.79(3H,s), 2.24(3H,s), 2.45(3H,s), 4.2-4.4(4H,m), 6.7-6.8(1H,m),              7.0-7.1(1H,m)                         233(M.sup.+ + 1)                                                                      0.30                              7.2-7.4(1H,m)                                                          023     2.30(3H,s), 2.33(3H,s), 2.41(3H,s), 2.3-2.7(10H,m), 3.54(2H,s),                4.0-4.2(2H,m),                        341(M.sup.+ + 1)                                                                      0.35                              7.30(5H,s)                                                             024     2.30(3H,s), 2.33(3H,s), 2.41(3H,s), 2.3-2.7(10H,m), 3.47(2H,s),                4.0-4.2(2H,m),                        375 377                                                                               0.36                              7.24(4H,s)                            (M.sup.+ + 1)                    025     2.30(3H,s), 2.34(3H,s), 2.41(3H,s), 2.57(8H,s), 2.5-2.7(2H,m),                 3.62(2H,s), 4.0-                      375 377                                                                               0.36                              4.2(2H,m), 7.1-7.5(4H,m)              (M.sup.+ + 1)                    026     2.29(3H,s), 2.35(3H,s), 2.38(3H,s), 3.4(1H,bs), 3.8-4.0(2H,m),                 4.1-4.3(2H,s)                         183(M.sup.+ + 1)                                                                      0.26                      027     2.21(3H,s), 2.25(3H,s), 2.38(3H,s), 3.1-3.3(2H,m), 4.1-4.3(2H,m),              7.1-7.6(5H,m)                         275(M.sup.+ + 1)                                                                      0.48                      028     2.32(3H,s), 2.43(3H,s), 2.46(3H,s), 3.4-3.7(2H,m), 3.95(3H,s),                 4.3-4.6(2H,m)                         281(M.sup.+ + 1)                                                                      0.39                      061     2.06(3H,s), 2.32(3H,s), 2.34(3H,s), 2.42(3H,s),                                4.31(2H,t,J≈3.3), 4.33(2H,t,J≈                                                                       225(M.sup.+ + 1)                                                                      0.31                              3.3)                                                                   062     2.31(3Hx2,s), 2.41(3H,s), 2.79(3H,d,J≈5.4),                            4.1-4.4(4H,m), 4.8-5.0(1H,bm)         240(M.sup.+ + 1)                                                                      0.31                      063     2.21(3H,s), 2.25(3H,s), 2.31(3H,s), 4.1-4.4(4H,m), 4.8-5.0(1H,b),              6.9-7.5(5H,m)                         302(M.sup.+ + 1)                                                                      0.41                      064     2.20(3H,s), 2.25(3H,s), 2.31(3H,s), 4.2-4.4(4H,m), 4.8-5.0(1H,b),              7.1-7.5(4H,m)                         388(M.sup.+ + 1)                                                                      0.42                                                                    336                              101     2.30(3Hx2,s), 2.33(3Hx2,s), 2.58(3Hx2,s), 2.58(8H,s),                          2.5-2.7(4H,m), 4.0-4.2(               415(M.sup.+ + 1)                                                                      0.13                              4H,m)                                                                  109     2.38(3H,s), 2.41(3H,s), 3.97(2H,t,J≈5.2),                              4.25(2H,t,J≈5.2), 7.2-7.5(3H,m), 8.1-                                                                        265(M.sup.+ + 1)                                                                      0.34                              8.2(2H,m)                                                              110     2.42(3Hx2,s), 2.4-2.8(6H,m), 3.6-3.8(4H,m), 4.25(2H,t,J≈6.             9), 7.3-7.5(3H,m),                    314(M.sup.+ + 1)                                                                      0.40                              8.1-8.3(2H,m)                         227                              111     2.41(3Hx2,s), 2.3-2.8(10H,m), 3.46(2H,s), 4.23(2H,t,J≈6.1)             , 7.27(4H,s), 7.2-                    441 439                                                                               0.40                              7.4(2H,m), 8.1-8.3(2H,m)              (M.sup.+ + 1)                    112     2.32(3Hx2,s), 3.90(2H,t,J=5.3), 4.08(2H,s), 4.20(2H,t,J=5.3),                  7.1-7.5(5H,m)                         258(M.sup.+ + 1)                                                                      0.34                      113     2.31(3Hx2,s), 2.4-2.7(6H,m), 3.5-3.7(4H,m), 4.08(2H,s),                        4.0-4.2(2H,m), 7.1-7.5                328(M.sup.+ + 1)                                                                      0.35                              (5H,m)                                241                                                                            114                              114     2.30(3Hx2,s), 2.3-2.7(10H,m), 3.51(2H,s), 4.08(2H,s),                          3.9-4.2(2H,m), 7.1-7.4(               417(M.sup.+ + 1)                                                                      0.32                              10H,m)                                                                 115     2.30(3Hx2,s), 2.3-2.7(10H,m), 3.45(2H,s), 4.08(2H,s),                          3.9-4.2(2H,m), 7.1-7.4(               452(M.sup.+ + 1)                                                                      0.35                              9H,m)                                 450                                                                            223                              116     2.31(3Hx2,s), 2.4-2.7(10H,m), 3.62(2H,s), 4.08(2H,s),                          4.0-4.2(2H,m), 7.1-7.9(               452(M.sup.+ + 1)                                                                      0.38                              9H,m)                                 450                                                                            223                              117     0.99(3H,t,J=7.3), 1.5-2.0(6H,m), 2.0-2.3(2H,m), 2.4-2.8(16H,m),                3.5-3.7(2H,m),                        349(M.sup.+ + 1)                                                                      0.08                              3.9-4.2(2H,m)                                                          118     0.99(3H,t,J=7.3), 1.5-2.0(6H,m), 2.4-2.9(12H,m), 3.5-3.8(4H,m),                3.9-4.2(2H,m)                         306(M.sup.+ + 1)                                                                      0.43                                                                    219                                                                            214                              119     0.98(3H,t,J≈7.3), 1.7-2.0(6H,m), 2.3-2.9(16H,m),                       3.51(2H,s), 3.9-4.2(2H,m),            395(M.sup.+ + 1)                                                                      0.40                              7.29(5H,s)                            189                              120     0.99(3H,t,J=7.3), 1.7-2.0(6H,m), 2.3-2.9(16H,m), 3.47(2H,s),                   3.9-4.2(2H,m),                        429(M.sup.+ + 1)                                                                      0.38                              7.26(4H,s)                            431                              121     0.99(3H,t,J=7.3), 1.5-1.0(2H,m), 2.31(3H,s), 2.33(3H,s), 2.4-                  2.8(8H,m), 3.6-                       280(M.sup.+ + 1)                                                                      0.33                              3.8(4H,m), 4.0-4.3(2H,m)              193                              122     0.98(3H,t,J=7.3), 1.5-1.9(2H,m), 2.30(2Hx3,s), 2.4-2.8(12H,m),                 3.51(2H,s),                           369(M.sup.+ + 1)                                                                      0.22                              4.0-4.2(2H,m), 7.29(5H,s)             193                              123     0.94(3Hx2,d,J=6.6), 1.9-2.4 (1H,m), 2.31(3H,s), 2.33(3H,s),                    2.4-2.7(8H,m), 3.6-                   294(M.sup.+ + 1)                                                                      0.40                              3.8(4H,m), 4.0-4.3(2H,m)              207                                                                            114                                                                            102                              124     0.93(3Hx2,d,J=6.6), 1.9-2.4(1H,m), 2.17(3H,s), 2.31(3H,s),                     2.4-2.7(12H,m), 3.51                  383(M.sup.+ + 1)                                                                      0.31                              (2H,s), 4.0-4.3(2H,m), 7.30(5H,s)     207                              125     0.93(3Hx2,d,J=6.6), 1.9-2.4(1H,m), 2.31(3Hx2,s), 2.3-2.8(12H,m),               3.46(2H,s),                           419(M.sup.+ + 1)                                                                      0.29                              4.0-4.3(2H,m), 7.26(4H,s)             417                                                                            207                                                                            125                              126     0.94(3Hx2,d,J=6.6), 1.9-2.4(1H,m), 2.31(3Hx2,s), 2.3-2.8(12H,m),               3.47(2H,s),                           419(M.sup.+ + 1)                                                                      0.31                              4.0-4.3(2H,m), 7.26(4H,s)             417                                                                            207                                                                            125                              127     0.95(3Hx2,d,J=6.6), 1.7-1.9(4H,m), 2.0-2.2(1H,m), 2.5-2.8(12H,m),              3.6-3.8(4H,                           320(M.sup.+ + 1)                                                                      0.39                              m), 4.0-4.2(2H,m)                     233                                                                            114                                                                            102                              128     0.94(3Hx2,d,J=6.6), 1.6-2.0(4H,m), 2.0-2.4(1H,m), 2.3-2.8(16H,m),              3.51(2H,s),                           409(M.sup.+ + 1)                                                                      0.38                              3.9-4.2(2H,m), 7.29(5H,s)             233                                                                            189                              129     0.94(3H,d,J=6.4), 0.96(3H,d,J=6.4), 1.6-2.0(4H,m), 2.0-2.4(1H,m),              2.3-2.8(16H,                          445(M.sup.+ + 1)                                                                      0.37                              m), 7.45(2H,s), 3.8-4.3(2H,m), 7.26(4H,s)                                                                            443                                                                            233                                                                            125                              130     0.99(3H,t,J=7.3), 1.21(3H,t,J=7.6), 1.23(2H, t,J=7.6),                         1.5-2.0(2H,m), 2.4-2.9                308(M.sup.+ + 1)                                                                      0.37                              (12H,m), 3.6-3.8(4H,m), 4.0-4.3(2H,m) 221                                                                            102                              131     0.99(3H,t,J=7.2), 1.20(3H,t,J=7.5), 1.4-1.0(2H,m),                             2.2-2.8(16H,m), 3.51(2H,              397(M.sup.+ + 1)                                                                      0.38                              s), 3.8-4.3(2H, m), 7.29(5H,s)        221                              132     0.99(3H,t,J=7.2), 1.21(3Hx2,t,J=7.6), 1.5-2.0(2H,m),                           2.3-2.9(16H,m), 3.48(2H,              433(M.sup.+ + 1)                                                                      0.31                              s), 3.9-4.3(2H,m), 7.26(4H,s)         431                                                                            307                                                                            221                                                                            125                              133     0.99(3H,t,J=7.2), 1.20(3Hx2,t,J=7.6), 1.4-2.1(2H,m),                           2.3-2.9(16H,m), 3.48(2H,              433(M.sup.+ + 1)                                                                      0.28                              s), 4.0-4.3(2H,m), 7.1-7.4(4H,m)      431                                                                            239                                                                            221                                                                            125                              134     0.99(3H,t,J=7.8), 1.20(3H,t,J=7.6), 1.21(3H,t,J≈7.6),                  1.4-2.1(2H,m), 2.4-2.9(               433(M.sup.+ + 1)                                                                      0.32                              16H,m), 2.64(2H,s), 4.0-4.3(2H,m), 7.1-7.5(4H,m)                                                                     431                                                                            221                                                                            125                              141     0.94(3H,t,J=6.4), 1.2-2.0(8H,m), 2.4-2.9(12H,m), 3.6- 3.8(4H,m),               3.9-4.2(2H,m)                         320(M.sup.+ + 1)                                                                      0.44                      142     0.93(3H,t,J≈6.4), 1.2-2.0(8H,m), 2.3-2.9(16H,m),                       3.51(2H,s), 3.9-4.3(2H,m),            409(M.sup.+ + 1)                                                                      0.47                              7.29(5H,s)                            189                              143     0.93(3H,t,J=6.4), 1.2-2.0(8H,m), 2.3-2.9(16H,m), 3.46(2H,s),                   3.9-4.2(2H,m),                        445(M.sup.+ + 1)                                                                      0.46                              7.26(4H,s)                            443                                                                            225                                                                            223                                                                            125                              144     0.93(3H,t,J=6.4), 1.2-2.0(14H,m), 2.4-2.9(12H,m),                                                                    318(M.sup.+ + 1)                                                                      0.33                                                                    223                                                                            111                              145     0.93(3H,t,J=6.4), 1.2-2.0(8H,m), 2.0-2.9(16H,m),                               3.61(2H,t,J=5.2), 3.9-4.2(2H,m)       363(M.sup.+ + 1)                                                                      0.09                                                                    143                                                                            125                              146     0.93(3H,t,J=6.4), 1.2-2.0(8H,m), 2.3-2.9(16H,m), 3.46(2H,s),                   3.9-4.2(2H,m),                        427(M.sup.+ + 1)                                                                      0.42                              6.8-7.1(2H,m), 7.1-7.3(2H,m)          207                              148     1.21(3Hx2,d,J=6.0), 2.32(3Hx2,s), 2.4-2.7(6H,m),                               3.42(1H,sept,J=6.9), 3.6-3.8          280(M.sup.+ + 1)                                                                      0.40                              (2H,m), 3.8-4.4(4H,m)                 114                              149     1.23(3H,d,J=6.9), 1.24(3H,d,J=6.9), 2.30(3H,s), 2.32(3H,s),                    2.3-2.7(10H,m),                       369(M.sup.+ + 1)                                                                      0.39                              3.42(1H,sept,J=6.9), 3.52(2H,s), 3.9-4.2(2H,m),                                                                      2049(5H,s)                       150     1.23(3H,d,J=6.9), 1.25(3H,d,J=6.9), 2.30(3H,s), 2.32(3H,s),                    2.3-2.7(10H,m),                       405(M.sup.+ + 1)                                                                      0.38                              3.42(1H,sept,J= 6.9), 3.46(2H,s), 3.8-4.3(2H,m),                                                                     4036(4H,s)                                                                     223                              151     1.23(3H,d,J=6.9), 1.24(3H,d,J=6.9), 2.30(3H,s), 2.32(3H,s),                    2.3-2.7(10H,m),                       413(M.sup.+ + 1)                                                                      0.39                              3.42(1H,sept,J=6.9), 3.47(2H,s), 3.9-4.2(2H,m), 6.8-7.1(2H,m),                 7.1-7.3(2H,m)                                                          152     0.88(3H,t,J=7.4), 1.11(3H,d,J=6.9), 1.3-2.0(2H,m), 2.32(3Hx2,s),               2.4-2.8(8H,m)                         294(M.sup.+ + 1)                                                                      0.44                              3.0-3.5(1H,m), 3.6-3.8(4H,m), 4.0-4.4(2H,m)                                                                          114                                                                            102                              153     0.88(3H,t,J=7.4), 1.17(3H,d,J=6.9), 1.2-2.0(2H,m), 2.30(3H,s),                 2.32(3H,s),                           383(M.sup.+ + 1)                                                                      0.38                              2.3-2.7(10H,m), 3.0-3.4(1H,m), 3.51(2H,s), 3.8-4.3(2H,m),                      7.29(5H,s)                            189                              154     0.88(3H,t,J=7.4), 1.17(3H,d,J=6.9), 1.2-2.0(2H,m), 2.31(3Hx2,s),               2.3-2.7(10H,                          419(M.sup.+ + 1)                                                                      0.34                              m), 3.0-3.5(1H,m), 3.47(2H,s), 3.8-4.3(2H,m), 7.26(4H,s)                                                             417                                                                            223                              155     0.88(3H,t,J=7.4), 1.17(3H,d,J=6.8), 1.3-2.0(2H,m), 2.31(3Hx2,s),               2.3-2.7(10H,                          401(M.sup.+ + 1)                                                                      0.36                              m), 3.0-3.5(1H,m), 3.47(2H,s), 4.0-4.3(2H,m), 7.1-7.3(2H,m)                                                          207                              156     0.94(3H,t,J=6.7), 1.2-1.8(4H,m), 2.31(3H,s), 2.33(3H,s),                       2.3-2.9(8H,m), 3.6-3.8                294(M.sup.+ + 1)                                                                      0.42                              (4H,m), 4.0-4.3(2H,m)                 207                                                                            114                                                                            102                              157     0.93(3H,t,J=6.7), 1.2-1.9(4H,m), 2.30(3H,s), 2.33(3H,s),                       2.3-2.9(12H,m), 3.51                  383(M.sup.+ + 1)                                                                      0.41                              (2H,s), 3.9-4.2(2H,m), 7.29(5H,s)     207                              158     0.93(3H,t,J=6.7), 1.2-1.8(4H,m), 2.30(3H,s), 2.32(3H,s),                       2.3-2.9(12H,m), 3.47                  419(M.sup.+ + 1)                                                                      0.46                              (2H,s), 3.9-4.3(2H,m), 7.26(4H,s)     417                                                                            207                                                                            125                              159     1.1-1.4(12H,m), 2.4-2.8(10H,m), 3.42(1H,sept,J=6.8),                           3.8-4.4(6H,m)                         308(M.sup.+ + 1)                                                                      0.47                                                                    239                                                                            113                              160     1.1-1.4(12H,m), 2.3-2.8(14H,m), 3.41(1H,sept,J=6.9), 3.52(2H,s),               3.8-4.3(2H,m),                        396(M.sup.+ + 1)                                                                      0.49                              7.29(5H,s)                            189                              161     1.1-1.4(12H,m), 2.4-2.8(14H,m), 3.41(1H,sept,J=6.8), 3.48(2H,s),               3.8-4.3(2H,m),                        433(M.sup.+ + 1)                                                                      0.48                              7.26(4H,s)                            431                                                                            236                                                                            223                                                                            125                              162     1.20(3Hx2,t,J=7.3), 1.21(3Hx2,d,J=6.8), 2.4-2.8(14H,m),                        3.41(1H,sept,J=6.8),                  415(M.sup.+ + 1)                                                                      0.43                              3.48(2H,s), 3.9-4.3(2H,m), 6.8-7.1(2H,m), 7.1-7.3(2H,m)                                                              207                              163     1.0-1.7(18H,m), 2.4-2.8(10H,m), 3.42(1H,sept,J=6.8),                           3.8-4.3(2H,m)                         306(M.sup.+ + 1)                                                                      0.44                                                                    239                                                                            221                              164     1.1-1.4(12H,m), 2.4-2.8(14H,m), 3.41(1H,sept,J=6.8), 3.48(2H,s),               3.9-4.3(2H,m),                        415(M.sup.+ + 1)                                                                      0.13                              6.8-7.1(2H,m), 7.1-7.3(2H,m)          207                              165     1.1-1.4(12H,m), 2.4-2.8(14H,m), 3.42(1H,sept,J=6.8), 3.48(2H,s),               3.8-4.3(2H,m),                        433(M.sup.+ + 1)                                                                      0.40                              7.1-7.3(4H,m)                         431                                                                            223                              166     0.94(3H,d,J=6.7), 0.95(3H,d,J=6.7), 1.20(3H,t,J=7.4),                          1.21(3H,t,J=7.4), 2.4-2.5             429(M.sup.+ + 1)                                                                      0.46                              (1H,sept,J=6.7), 2.3-2.9(16H,m), 3.48(2H,s), 3.8-4.3(2H,m),                    6.8-7.1(2H,m), 7.1-                   220                                      7.4(2H,m)                             207                              167     0.95(3Hx2,d,J=6.4), 1.21(3Hx2,t,J=7.4), 2.0-2.4(1H,m),                         2.4-2.8(12H,m), 3.5-3.8               322(M.sup.+ + 1)                                                                      0.41                              (4H,m), 4.0-4.3(2H,m)                                                  168     0.94(3H,d,J=6.7), 0.95(3H,d,J=6.7), 1.20(3H,t,J=7.3),                          1.21(3H,t,J=7.3), 2.0-2.5             447(M.sup.+ + 1)                                                                      0.44                              (1H,m), 2.3-2.9(16H,m), 3.47(2H,s), 3.9-4.3(2H,m),                                                                   4456(4H,s)                                                                     223                              170     0.94(3Hx2,d,J=6.7), 1.20(3H,t,J=6.7), 1.21(3H,t,J=6.5),                        2.0-2.4(1H,m), 2.3-2.8                411(M.sup.+ + 1)                                                                      0.36                              (16H,m), 3.51(12H,s), 4.0-4.3(2H,m), 7.29(5H,m)                                                                      189                              171     0.88(3H,t,J=7.4), 1.17(3H,d,J=6.8), 1.22(3Hx2,t,J=7.2),                        1.3-2.0(8H,m), 2.4-2.8                320(M.sup.+ + 1)                                                                      0.38                              (10H,m), 3.0-3.4(1H,m), 4.1-4.3(2H,m) 111                              172     0.88(3H,t,J=7.3), 1.17(3H,d,J=6.3), 1.21(3Hx2,t,J=7.2),                        1.4-2.0(2H,m), 2.3-2.8                365(M.sup.+ + 1)                                                                      0.09                              (6H,m), 3.1-3.3(1H,m), 3.61(2H,t,J≈5.4),                                                                     156-4.3(2H,m)                    173     0.88(3H,t,J=7.5), 1.17(3H,d,J=6.8), 1.21(3Hx2,t,J=7.1),                        1.2-1.9(2H,m), 2.4-2.8                322(M.sup.+ + 1)                                                                      0.42                              (10H,m), 3.1-3.4(1H,m), 3.6-4.0(4H,m), 4.0-4.3(2H,m)                                                                 103                              174     0.87(3H,t,J=7.2), 1.16(3H,d,J=6.8), 1.20(3Hx2,t,J=6.6),                        1.3-1.9(2H,m), 2.4-2.8                411(M.sup.+ + 1)                                                                      0.43                              (14H,m), 3.0-3.4(1H,m), 3.53(2H,s), 4.1-4.3(2H,m), 7.30(5H,s)          175     0.87(3H,t,J=7.4), 1.1-1.3(9H,m), 1.3-2.0(2H,m), 2.4-2.7(14H,m),                3.0-3.4(1H,m),                        429(M.sup.+ + 1)                                                                      0.42                              3.47(2H,s), 3.9-4.3(2H,m), 6.8-7.1(2H,m), 7.1-7.3(2H,m)                                                              220                              176     0.88(3H,t,J=7.6), 1.17(3H,d,J=7.1), 1.21(3Hx2,t,J=7.1),                        1.4-2.0(2H,m), 2.3-2.8                447(M.sup.+ + 1)                                                                      0.42                              (14H,m), 3.0-3.4(1H,m), 3.47(2H,s), 4.0-4.3(2H,m),                                                                   4456(4H,s)                                                                     223                              177     0.87(3H,t,J=7.2), 1.17(3H,d,J=6.8), 1.21(3Hx2,t,J=6.9),                        1.2-2.0(2H,m), 2.3-2.8                447(M.sup.+ + 1)                                                                      0.39                              (14H,m), 3.1-3.4(1H,m), 3.48(2H,s), 4.0-4.3(2H,m),                                                                   445-7.4(4H,m)                                                                  223                              178     0.93(3H,t,J=6.4), 1.20(3Hx2,t,J=7.4), 1.2-1.9(4H,m),                           2.2-2.9(16H,m), 3.63(2H,              447(M.sup.+ + 1)                                                                      0.43                              s), 3.9-4.3(2H,m), 7.1-7.5(4H,m)      445                                                                            223                              179     0.93(3H,t,J=6.4), 1.20(3Hx2,t,J=7.5), 1.2-1.9(4H,m),                           2.2-2.8(16H,m), 3.52(2H,              411(M.sup.+ + 1)                                                                      0.46                              s), 3.9-4.3(2H,m), 7.29(5H,s)         189                              180     0.93(3H,t,J=6.4), 1.21(3Hx2,t,J=7.4), 1.2-1.9(4H,m),                           2.2-2.9(16H,m), 3.47(2H,              447(M.sup.+ + 1)                                                                      0.43                              s), 3.9-4.3(2H,m), 7.26(4H,s)         445                                                                            223                              181     0.94(3H,t,J=6.6), 1.20(3H,t,J=7.6), 1.23(3H,t,J=7.6),                          1.2-1.9(10H,m), 2.4-2.9               320(M.sup.+ + 1)                                                                      0.40                              (12H,m), 4.1-4.4(2H,m)                                                 182     0.94(3H,t,J=6.6), 1.21(3H,t,J=7.6), 1.23(3H,t,J=7.6),                          1.2-1.9(4H,m), 2.4-2.9(               322(M.sup.+ + 1)                                                                      0.39                              12H,m), 3.6-4.0(4H,m), 3.9-4.3(2H,m)  113                              183     0.93(3H,t,J=6.6), 1.20(3Hx2,t,J=7.5), 1.2-1.8(4H,m),                           2.3-2.9(16H,m), 3.47(2H,              429(M.sup.+ + 1)                                                                      0.42                              s), 3.9-4.3(2H,m), 6.8-7.1(2H,m), 7.1-7.4(2H,m)                                                                      207                              185     0.94(3H,t,J=6.4), 1.21(3Hx2,t,J=7.4), 1.2-1.8(4H,m),                           2.2-2.9(16H,m), 3.48(2H,              447(M.sup.+ + 1)                         s), 4.0-4.3(2H,m)                     445                                                                            223                              187     1.22(3Hx2,t,J=7.3), 1.23(3H,t,J=7.3), 2.4-2.9(12H,m),                          3.6-3.8(4H,m), 3.8-4.3(               294(M.sup.+ + 1)                                                                      0.39                              2H,m),                                207                              188     1.21(3Hx2,t,J=7.3), 1.22(3H,t,J=7.3), 2.3-2.9(16H,m), 3.48(2H,s),              3.8-4.3(2H,                           419(M.sup.+ + 1)                                                                      0.40                              m), 7.26(4H,s)                        417                                                                            225                              189     1.21(3Hx2,t,J=7.3), 1.22(3H,t,J=7.3), 2.4-2.9(16H,m), 3.54(2H,s),              3.8-4.3(2H,                           383(M.sup.+ + 1)                                                                      0.40                              m), 7.29(5H,s)                        189                              190     1.23(3H,t,J=7.5), 2.32(3Hx2,s), 2.2-2.7(6H,m), 2.78(2H,q,J=7.5),               3.6-3.8(4H,m),                        266(M.sup.+ + 1)                                                                      0.56                              4.16(2H,t,J=7.2)                      179                                                                            174                              191     1.22(3H,t,J=7.5), 2.31(3Hx2,s), 2.3-2.7(10H,m), 2.78(2H,q,J=7.5),              3.46(2H,s),                           391(M.sup.+ + 1)                                                                      0.49                              3.9-4.3 (2H,m), 7.26(4H,s)            389                              192     1.22(3H,t,J=7.5), 2.31(3H,s), 2.33(3H,s), 2.3-2.7(10H,m),                      2.78(2H,q,J=7.5),                     373(M.sup.+ + 1)                                                                      0.42                              3.47(2H,s), 3.9-4.3(2H,m), 6.8-7.3(4H,m)                                                                             207                                                                            179                              193     1.22(3H,t,J=7.5), 2.31(3H,s), 2.33(3H,s), 2.3-2.7(10H,m),                      2.78(2H,q,J=7.5),                     385(M.sup.+ + 1)                                                                      0.50                              3.45(2H,s), 3.79(3H,s), 3.8-4.2(2H,m), 6.7-6.9(2H,m),                          7.1-7.3(2H,m)                         219                              250     0.89(3H,t,J≈6.5), 1.1-1.9(10H,m), 2.3-2.8(16H,m),                      3.47(2H,s), 3.8-4.2(2H,m),            459(M.sup.+ + 1)                                                                      0.36                              7.26(4H,s)                            457                                                                            247                                                                            223                              251     0.89(3H,t,J≈6.5), 1.1-1.9(10H,m), 2.3-2.8(16H,m),                      3.48(2H,s), 3.8-4.2(2H,s),            441(M.sup.+ + 1)                                                                      0.35                              6.8-7.3(4H,m)                         247                                                                            207                              252     0.89(3H,t,J≈6.5), 1.1-1.5(4H,m), 1.5-1.9(6H,m),                        2.4-2.8(12H,m), 3.5-3.7(4H,m),        334(M.sup.+ + 1)                                                                      0.35                              3.8-4.2(2H,m)                         114                              253     0.8-1.0(6H,m), 1.1-1.9(14H,m), 2.2-2.8(18H,m), 3.9-4.1(2H,m)                                                         389(M.sup.+ + 1)                                                                      0.29                                                                    155                                                                            125                              254     0.89(3H,t,J≈6.5), 1.1-1.9(10H,m), 2.3-2.8(16H,m),                      3.47(2H,s), 3.80(3H,s), 3.8-          453(M.sup.+ + 1)                                                                      0.34                              4.2(2H,m), 6.84(2H,d,J=8.6), 7.22(2H,d,J=8.6)                                                                        247                                                                            219                                                                            111                              255     0.88(3H,t,J≈6.3), 1.1-1.9(12H,m), 2.4-2.9(12H,m),                      3.6-3.8(4H,m), 3.9-4.2(2H,m)          348(M.sup.+ + 1)                                                                      0.51                                                                    113                              256     0.87(3H,t,J≈6.3), 1.1-1.9(12H,m), 2.3-2.8(16H,m),                      3.47(2H,s), 3.9-4.2(2H,m),            473 471                                                                               0.49                              7.26(4H,s)                            (M.sup.+ + 1)                                                                  238                                                                            236                                                                            112                              257     0.87(3H,t,J≈6.3), 1.1-1.9(12H,m), 2.3-2.8(16H,m),                      3.59(2H,s), 3.9-4.2(2H,m),            482(M.sup.+ + 1)                                                                      0.42                              7.50(2H,d,J=8.8), 8.16(2H,d,J=8.8)    347                                                                            234                                                                            112                              258     0.87(3H,t,J≈6), 1.2-2.0(14H,m), 2.5-2.9(16H,m),                        3.60(2H,s), 3.9-4.2(2H,s),            469(M.sup.+ + 1)                                                                      0.46                              6.8-7.4(4H,m)                         235                                                                            221                              259     0.87(3H,t,J=6.5), 1.1-1.9(14H,m), 2.4-2.9(12H,m), 3.4-3.8(4H,m),               3.9-4.2(2H,m)                         362(M.sup.+ + 1)                                                                      0.41                                                                    114                              260     0.87(3H,t,J≈6), 1.1-1.9(14H,m), 2.3-2.9(16H,m),                        3.47(2H,s), 3.9-4.2(2H,m),            485 487                                                                               0.40                              7.26(4H,s)                            (M.sup.+ + 1)                                                                  223                              261     0.87(3H,t,J≈6), 1.1-1.9(14H,m), 2.4-2.8(16H,m),                        3.59(2H,s), 3.9-4.2(2H,m),            496(M.sup.+ + 1)                                                                      0.46                              7.49(2H,d,J≈8.8), 8.17(2H,d,J=8.8)                                                                           234                              262     0.87(3H,t,J≈6), 1.1-1.9(14H,m), 2.3-2.9(16H,m),                        3.49(2H,s), 3.9-4.1(2H,m),            469(M.sup.+ + 1)                                                                      0.42                              6.8-7.3(4H,m)                         275                                                                            207                              263     0.8-1.0(6H,m), 1.1-1.6(12H,m), 1.5-1.9(6H,m), 2.1-2.9(18H,m),                  3.9-4.2(2H,m)                         417(M.sup.+ + 1)                                                                      0.43                                                                    155                              264     0.87(3H,t,J=6), 1.1-2.0(16H,m), 2.5-2.9(16H,m), 3.59(2H,s),                    3.9-4.2(2H,m),                        498 500                                                                               0.45                              7.27(4H,s)                            (M.sup.+ + 1)                                                                  250                                                                            237                              265     0.87(3H,t,J≈6), 1.1-1.9(16H,m), 2.4-2.9(12H,m),                        3.6-3.8(4H,m), 3.9-4.2(2H,m)          376(M.sup.+ + 1)                                                                      0.47                                                                    114                              266     0.87(3H,t,J≈6), 1.1-1.9(16H,m), 2.3-2.9(16H,m),                        3.47(2H,s), 3.9-4.2(2H,m),            499 501                                                                               0.43                              7.26(4H,s)                            (M.sup.+ + 1)                                                                  289                                                                            223                              267     0.87(3H,t,J≈6), 1.1-2.0(16H,m), 2.3-2.9(16H,m),                        3.46(2H,s), 3.80(3H,s), 3.9-          495(M.sup.+ + 1)                                                                      0.42                              4.1(2H,m), 6.84(2H,d,J=8.6), 7.22(2H,d,J=8.6)                                                                        232                              268     0.87(3H,t,J≈6), 1.1-2.0(16H,m), 2.3-2.9(16H,m),                        3.59(2H,s), 3.8-4.2(2H,m), 7.5        510(M.sup.+ + 1)                                                                      0.46                              (2H,d,J=8.8), 8.17(2H,d,J=8.8)        234                              269     0.87(3H,t,J≈6), 1.1-2.0(16H,m), 2.3-2.9(16H,m),                        3.47(2H,s), 3.9-4.2(2H,m), 6.8        483(M.sup.+ + 1)                                                                      0.51                              -7.3(4H,m)                            289                                                                            207                              270     0.87(3H,t,J≈6), 1.1-2.0(18H,m), 2.5-2.9(16H,m),                        3.59(2H,s), 3.9-4.1(2H,m), 6.8        497(M.sup.+ +                                                                         0.45                              -7.3(4H,m)                            235                                                                            221                              271     0.87(3H,t,J≈6), 1.1-1.9(18H,m), 2.4-2.9(12H,m),                        3.6-3.8(4H,m), 3.9-4.2(2H,m)          390(M.sup.+ + 1)                                                                      0.48                      272     0.87(3H,t,J≈6), 1.1-1.9(18H,m), 2.3-2.9(16H,m),                        3.46(2H,s), 3.9-4.2(2H,m),            513 515                                                                               0.51                              7.26(4H,s)                            (M.sup.+ + 1)                                                                  223                              273     0.87(3H,t,J≈6), 1.1-1.9(18H,m), 2.4-2.9(16H,m),                        3.46(2H,s), 3.9-4.2(2H,m), 6.8        497(M.sup.+ + 1)                                                                      0.48                              -7.3(4H,m)                            207                              274     0.87(3H,t,J≈6), 1.1-1.9(18H,m), 2.3-2.9(16H,m),                        3.59(2H,s), 3.9-4.3(2H,m),            524(M.sup.+ + 1)                                                                      0.52                              7.50(2H,d,J=8.8), 8.17(2H,d,J=8.8)    247                                                                            234                              275     0.87(3H,t,J≈6), 1.1-2.0(18H,m), 2.3-2.9(16H,m),                        3.47(2H,s), 3.80(3H,s), 3.9-          509(M.sup.+ + 1)                                                                      0.43                              4.2(2H,m), 6.85(2H,d,J=8.8), 7.23(2H,d,J=8.8)                                                                        232                                                                            219                              276     0.87(3H,t,J≈6), 1.1-1.9(24H,m), 2.4-2.9(12H,m),                        3.6-3.8(4H,m), 3.9-4.2(2H,m)          432(M.sup.+ + 1)                                                                      0.45                      277     0.87(3H,t,J≈6), 1.1-2.0(24H,m), 2.3-2.9(16H,m),                        3.47(2H,s), 3.9-4.2(2H,m),            555 557                                                                               0.44                              7.26(4H,s)                            (M.sup.+ + 1)                                                                  345                                                                            236                                                                            223                              278     0.87(3H,t,J≈6), 1.1-2.0(26H,m), 2.5-2.9(16H,m),                        3.59(2H,s), 3.9-4.1(2H,m), 6.8        553(M.sup.+ + 1)                                                                      0.46                              -7.3(4H,m)                            235                                                                            221                              279     0.87(3H,t,J≈6), 1.1-2.0(24H,m), 2.3-2.9(16H,m),                        3.58(3H,s), 3.9-4.3(2H,m),            566(M.sup.+ + 1)                                                                      0.47                              7.49(2H,d,J=8.6), 8.17(2H,d,J=8.6)    431                                                                            247                                                                            112                              280     0.88(3H,t,J≈6), 1.1-1.9(28H,m), 2.4-2.9(12H,m),                        3.5-3.7(4H,m), 3.9-4.2(2H,m)          460(M.sup.+ + 1)                                                                      0.53                                                                    114                              281     0.88(3H,t,J≈6), 1.1-2.0(28H,m), 2.3-2.9(16H,m),                        3.45(2H,s), 3.79(3H,s), 3.9-          579(M.sup.+ + 1)                                                                      0.44                              4.2(2H,m), 6.84(2H,d,J=8.7), 7.22(2H,d,J=8.7)                                                                        232                                                                            219                              282     0.88(3H,t,J≈6), 1.1-2.0(30H,m), 2.5-2.9(16H,m),                        3.59(3H,s), 3.9-4.1(2H,m), 6.8        581(M.sup.+ + 1)                                                                      0.50                              -7.3(4H,m)                            234                                                                            221                              283     0.88(3H,t,J≈6), 1.1-1.7(32H,m), 2.4-2.9(12H,m),                        3.5-3.7(4H,m), 3.9-4.2(2H,m)          488(M.sup.+ + 1)                                                                      0.54                                                                    114                              284     0.88(3H,t,J≈6), 1.1-2.0(32H,m), 2.3-2.9(16H,m),                        3.46(2H,s), 3.9-4.2(2H,m),            611 613                                                                               0.50                              7.26(4H,s)                            (M.sup.+ + 1)                                                                  279                                                                            236                              285     0.88(3H,t,J≈6), 1.1-2.0(32H,m), 2.3-2.9(16H,m),                        3.58(2H,s), 3.9-4.2(2H,m),            622(M.sup.+ + 1)                                                                      0.50                              7.49(2H,d,J=8.8), 8.19(2H,d,J=8.8)    419                                                                            208                              286     0.88(3H,t,J≈6), 1.1-2.0(34H,m), 2.5-2.9(16H,m),                        3.59(2H,s), 3.8- 4.1(2H,m),           627 625                                                                               0.48                              7.26(4H,s)                            (M.sup.+ + 1)                                                                  307                                                                            250                              287     1.23(3H,t,J=7.5), 2.31(3Hx2,s), 2.3-3.0(12H,m), 3.51(2H,s),                    3.9-4.3(2H,m),                        355(M.sup.+ + 1)                                                                      0.49                              7.29(5H,s)                            179                              288     1.23(3H,t,J=7.5), 1.6-1.9(2H,m), 2.31(3Hx2,s), 2.4-3.0(12H,m),                 3.59(2H,s),3.9                        391(M.sup.+ + 1)                                                                      0.40                              -4.2(2H,m), 7.27(4H,s)                389                              289     1.23(3H,t,J=7.5), 1.6-1.9(2H,m), 2.31(3Hx2,s), 2.4-3.0(12H,m),                 3.60(2H,s),                           387(M.sup.+ + 1)                                                                      0.39                              3.9-4.2(2H,m), 6.8-7.4(4H,m)          225                                                                            221                                                                            179                              290     1.23(3H,t,J=7.5), 2.31(3Hx2,s), 2.3-3.0(12H,m), 3.59(2H,s),                    3.9-4.3(2H,m),                        400(M.sup.+ + 1)                                                                      0.44                              7.50(2H,d,J=8.7), 8.17(2H,d,J=8.7)    234                                                                            179                              291     1.21(3Hx2,t,J=7.6), 2.4-2.8(10H,m), 3.5-3.7(2H,m), 3.8-4.2(4H,m),              4.09(2H,s),                           356    0.36                              7.0-7.4(5H,m)                                                          292     1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 1.3-1.8(6H,m),                             2.3-2.8(10H,m), 3.8-4.3(2H,           354    0.40                              m), 4.09(2H,s), 7.0-7.5(5H,m)                                          293     1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.3-2.8(14H,m), 3.50(2H,s),                3.8-4.2(2H,m),                        444    0.36                              4.08(2H,s), 7.0-7.4(10H,m)            202                                                                            189                              294     1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.3-2.8(14H,m), 3.45(2H,s)                 3.8-4.2(2H,m),                        479, 481                                                                              0.36                              4.08(2H,s), 7.0-7.4(9H,m)             236                              295     1.19(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.3-2.8(14H,m), 3.56(2H,s),                4.09(2H,s),                           513,515                                                                               0.60                              3.8- 4.2(2H,m), 7.0-7.4(8H,m)         517                                                                            237                                                                            219                              296     1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.2.2.8(14H,m), 3.45(2H,s),                3.8-4.2(2H,m),                        462    0.37                              4.08(2H,s), 6.8-7.4(9H,m)             207                              297     1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.2-2.7(14H,m), 3.43(2H,s),                3.79(3H,s),                           474    0.37                              3.8-4.2(2H,m), 4.08(2H,s), 6.83(2H,d,J=8.8), 7.0-7.4(7H,m)                                                           232                                                                            219                              305     0.87(3H,t,J≈5.7), 1.2-2.0(12H,m), 2.4-2.9(12H,m),                      3.0-3.4(6H,m), 4.0-4.3(2H,            423,422                                                                               0.65                              m), 7.1-7.3(5H,m)                     174                              306     0.87(3H,t,J≈5.7), 1.2-2.0(12H,m), 2.3-2.9(16H,m),                      3.51(2H,s), 3.9-4.2(2H,m),            437    0.36                              7.29(5H,s)                            189                              307     0.87(3H,t,J≈5.7), 1.2-2.0(12H,m), 2.3-2.9(16H,m),                      3.46(2H,s), 3.9-4.2(2H,m),            455    0.38                              6.8-7.4(14H,m)                        207                              308     0.87(3H,t,J≈5.7), 1.2-2.0(12H,m), 2.3-2.9(16H,m),                      3.45(2H,s), 3.79(3H,s), 3.9-          467    0.40                              4.2(2H,m), 6.84(2H,d,J=8.6), 7.22(2H,d,J=8.6)                                                                        219                              309     0.87(3H,t,J≈5.7), 1.2-2.0(12H,m), 2.6-2.9(12H,m),                      3.0-3.2(4H,m), 4.0-4.3(2H,            457,459                                                                               0.36                              m), 6.8-7.4(4H,m)                     209                              310     0.87(3H,t,J≈5.7), 1.2-2.0(12H,m), 2.6-2.9(12H,m),                      3.0-3.2(4H,m), 3.89(3H,s),            453    0.53                              4.0-4.3(2H,m), 7.7-8.1(4H,m)          203                              311     0.87(3H,t,J≈5.6), 1.2-2.0(14H,m), 2.6-3.0(16H,m),                      3.72(2H,s), 3.9-4.2(2H,m),            496    0.43                              7.51(2H,d,J=8.8), 8.17(2H,d,J=8.8)    301                                                                            248                              312     0.87(3H,t,J≈5.6), 1.2-2.0(14H,m), 2.5-3.0(16H,m),                      3.59(2H,s), 3.9-4.2(2H,m),            485,487                                                                               0.49                              7.28(4H,s)                            237                              313     0.87(3H,t,J≈5.7), 1.2-2.0(14H,m), 2.6-2.9(16H,m),                      3.58(2H,s), 3.80(3H,s), 3.9-          481    0.48                              4.2(2H,m), 6.84(2H,d,J=8.8), 7.24(2H,d, J=8.8)                                                                       247                                                                            233                              314     0.87(3H,t,J≈5.7), 1.1-1.9(14H,m), 2.3-2.9(16H,m),                      3.51(2H,s), 3.9-4.1(2H,m),            451    0.48                              7.30(5H,s)                            189                              315     0.87(3H,t,J≈5.6), 1.1-1.9(14H,m),2.5-2.9(12H,m),                       3.1-3.3(4H,m), 4.0-4.2(2H,m),         437    0.60                              6.7-8.3(5H,m)                         189                                                                            175                              316     0.87(3H,t,J≈5.6), 1.1-2.0(14H,m), 2.5-2.9(12H,m),                      2.9-3.2(4H,m), 3.86(3H,s),            467    0.65                              3.9-4.2(2H,m), 6.7-7.1(4H,m)          203                              317     0.87(3H,t,J≈5.6), 1.1-2.0(14H,m), 2.5-2.9(12H,m),                      2.9-3.2(4H,m), 4.0-4.2(2H,            471,473                                                                               0.72                              m), 6.7-7.4(4H,m)                     209                              318     0.87(3H,t,J≈5.6), 1.1-2.0(16H,m), 2.5-2.9(16H,m),                      3.59(2H,s), 3.9-4.1(2H,m),            483    0.40                              6.8-7.3(4H,m)                         221                              319     0.87(3H,t,J≈5.6), 1.2-2.0(16H,m), 2.5-3.0(16H,m),                      3.58(2H,s), 3.8(3H,s), 3.9-           495    0.44                              4.2(2H,m), 6.84(2H,d,J=8.8), 7.24(2H,d,J=8.8)                                                                        246,247                          320     0.87(3H,t,J≈5.6), 1.1-2.0(16H,m), 2.5-2.9(16H,m),                      3.72(2H,s), 3.9-4.1(2H,m),            510    0.45                              7.51(2H,d,J=8.8), 8.17(2H,d,J=8.8)                                     321     0.87(3H,t,J≈5.6), 1.0-2.0(16H,m), 2.3-2.8(16H,m),                      3.51(2H,s), 3.9-4.2(2H,m),            465    0.50                              7.29(5H,s)                            189                              322     0.87(3H,t,J≈6), 1.0-2.0(16H,m), 2.5-2.9(12H,m),                        3.0-3.3(4H,m), 4.0-4.2(2H,m),         451    0.55                              6.7-7.4(5H,m)                         175                              323     0.87(3H,t,J≈6), 1.1-2.0(16H,m), 2.5-2.9(12H,m),                        2.9-3.2(4H,m), 3.58(3H,s),            481    0.57                              4.0-4.2(2H,m), 6.7-7.1(4H,m)          205                              324     0.87(3H,t,J≈6), 1.0-2.0(16H,m), 2.5-2.9(12H,m),                        2.9-3.2(4H,m), 4.0-4.2(2H,m),         485,487                                                                               0.52                              6.8-7.4(4H,m)                         209                              325     0.87(3H,t,J≈5.6), 1.1-2.0(18H,m), 2.5-3.0(16H,m),                      3.72(2H,s), 3.9-4.2(2H,m),            523    0.41                              7.51(2H,d,J≈8.8), 8.17(2H,d,J=8.8)                                                                           339                                                                            248                              326     0.87(3H,t,J≈6), 1.1-2.2(18H,m), 2.5-3.0(16H,m),                        3.58(2H,s), 3.80(3H,s), 3.9-          509    0.41                              4.2(2H,m), 6.84(2H,d,J=8.8), 7.24(2H,d,J=8.8)                                                                        247                                                                            233                              327     0.87(3H,t,J≈6), 1.1-2.2(18H,m), 2.5-3.0(16H,m),                        3.59(2H,s), 3.9-4.2(2H,m),            513,515                                                                               0.43                              7.26(4H,s)                            237                              328     0.87(3H,t,J≈6), 1.2-2.2(18H,m), 2.4-2.9(16H,m),                        3.51(2H,s), 3.9-4.2(2H,m),            479    0.48                              7.29(5H,s)                            189                              329     0.87(3H,t,J≈6), 1.1-2.1(20H,m), 2.4-3.0(16H,m),                        3.59(2H,s), 3.9-4.2(2H,m),            527,529                                                                               0.49                              7.26(4H,s)                            237                              330     0.87(3H,t,J≈6), 1.1-2.2(20H,m), 2.5-3.0(16H,m),                        3.72(2H,s), 3.9-4.2(2H,m),            538    0.51                              7.51(2H,d,J≈8.8), 8.17(2H,d,J=8.8)                                                                           402                              331     0.87(3H,t,J≈6), 1.1-2.2(20H,m), 2.5-3.0(16H,m),                        3.60(2H,s), 3.9-4.2(2H,m),            511    0.45                              6.8-7.4(4H,m)                         220                              332     0.87(3H,t,J≈6), 1.1-2.2(20H,m), 2.5-3.0(16H,m),                        3.58(2H,s), 3.80(3H,s), 3.9-          523    0.43                              4.2(2H,m), 6.84(2H,d,J=8.4), 7.24(2H,d,J=8.4)                                                                        247                                                                            233                              334     0.87(3H,t,J≈6), 1.1-2.0(20H,m), 2.3-2.9(12H,m),                        3.5-3.8(4H,m), 3.9-4.2(2H,m)          404    0.46                                                                    102                              335     0.87(3H,t,J≈6), 1.1-2.2(20H,m), 2.3-2.9(16H,m),                        3.51(2H,s), 3.9-4.2(2H,m),            493    0.47                              7.29(5H,s)                            189                              336     0.87(3H,t,J≈6), 1.0-2.0(20H,m), 2.5-2.9(12H,m),                        3.0-3.3(4H,m), 3.9-4.2(2H,m),         479    0.54                              6.7-7.4(4H,m)                         190                                                                            175                              337     0.87(3H,t,J≈6), 1.0-2.0(20H,m), 2.1-2.9(16H,m),                        3.45(2H,s), 3.79(3H,s), 3.9-          523    0.47                              4.2(2H,m), 6.84(2H,d,J=8.8), 7.12(2H,d,J=8.8)                                                                        232                                                                            219                              338     0.87(3H,t,J≈6), 1.0-2.2(20H,m), 2.3-2.9(16H,m),                        3.9-4.2(2H,m), 7.26(4H,s)             527,529                                                                               0.48                                                                    235                                                                            223                              339     0.87(3H,t,J≈6), 1.0-2.0(22H,m), 2.5-3.0(16H,m),                        3.72(2H,s), 3.9-4.2(2H,m),            552    0.49                              7.51(2H,d,J=8.8), 8.17(2H,d,J=8.8)    417                                                                            248                              340     0.87(3H,t,J≈6), 1.1-2.1(22H,m), 2.5-3.0(16H,m),                        3.60(2H,s), 3.9-4.2(2H,m),            541,543                                                                               0.48                              7.27(4H,s)                            251                                                                            237                              374     1.21(3Hx2,t,J=7.6), 1.7-2.0(4H,m), 2.1-3.3(11H,m), 4.10(2H,s),                 4.1-4.3(2H,m),                        430    0.74                              7.1-7.5(10H,m)                        134                              375     0.91(3H,d,J=4.9), 1.19(3H,t,J=7.7), 1.20(3H,t,J=7.7),                          1.4-2.3(5H,m), 2.4-3.0                368    0.53                              (10H,m), 3.9-4.2(2H,m), 4.09(2H,s), 7.1-7.5(5H,m)                                                                    112                              378     1.19(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.4-2.7(14H,m), 3.58(2H,s),                4.09(2H,s),                           490    0.49                              3.8-4.3(2H,m), 7.1-7.5(7H,m), 8.16(2H,d,J=8.8)                                                                       247                                                                            191                              380     1.21(3Hx2,t,J≈7.6),2.4-3.6(14H,m),4.10(2H,s),                          4.0-4.4(2H,m), 6.8-7.5(10H,m)         431    0.63                                                                    188,189                                                                        175                              384     1.20(3Hx2,t,J≈7.4),2.2-2.8(10H,m), 3.6-4.3(6H,m),                      4.04(2H,s), 7.1-7.4(4H,m)             392    0.43                                                                    390                                                                            114                              385     1.19(3Hx2,t,J≈7.6), 2.2-2.8(14H,m), 3.46(2H,s),                        3.8-4.3(2H,m), 4.04(2H,s), 7.1        517    0.48                              -7.4(8H,m)                            515                                                                            513                                                                            303                                                                            223                              386     1.19(3Hx2,t,J≈7.6), 2.1-2.8(14H,m), 3.46(2H,s),                        3.79(3H,s), 3.9-4.2(2H,m),            511    0.42                              4.03(2H,s), 6.84(2H,d,J≈8.8), 7.1-7.4(6H,m)                                                                  509                                                                            232                                                                            219                              387     1.19(3H,t,J=7.1), 1.20(3H,t,J=7.1), 2.3-2.8(14H,m), 3.47(2H,s),                4.05(2H,s),                           526    0.43                              4.1-4.3(2H,m), 7.52(2H,d,J=8.8), 7.26(4H,s), 8.17(2H,d,J=8.8)                                                        524                                                                            247                              454     1.23(3H,t,J≈7.4), 2.32(3H,s), 2.33(3H,s), 2.4-3.0(13H,m),              4.0-4.2(2H,m)                         265                                                                            179                              455     1.22(3H,t,J≈7.4), 2.30(3Hx2,s), 2.2-3.0(8H,m),                         3.44(2H,t,J≈5), 3.65(2H,t,J≈5),                                                                      383                                      3.72(2H,s), 4.0-4.2(2H,m), 7.1-7.4(5H,m)                                                                             217                                                                            139                              456     1.22(3H,t,J=7.4), 2.32(3Hx2,s), 2.4-2.9(8H,m), 3.3-3.8(4H,m),                  4.0-4.3(2H,m),                        405                                      7.36(4H,s)                            403                                                                            251                                                                            237                              457     1.23(3H,t,J=7.4), 2.31(3Hx2,s), 2.3-2.9(8H,m), 3.51(2H,t,J.apprxeq             .5), 3.65(2H,t,J≈5),          389                                      3.90(2H,s), 4.0-4.2(2H,m), 6.8-7.3(3H,m)                                                                             223                              458     1.22(3H,t,J=7.4), 2.32(3Hx2,s), 2.4-3.0(8H,m), 3.2-3.5(2H,m),                  3.5-3.9(2H,m),                        414                                      4.0-4.3(2H,m), 7.56(2H,d,J≈8.8), 8.23(2H,d,J=8.8)                                                            262                                                                            248                              459     1.23(3H,t,J=7.4), 2.31(3Hx2,s), 2.4-3.0(8H,m), 3.48(2H,t,J.apprxeq             .5), 3.65(2H,t,J=5),                  428                                      3.81(2H,s), 4.0-4.3(2H,m), 7.41(2H,d,J=8.6), 8.19(2H,d,J=8.6)                                                        265                              460     1.23(3H,t,J=7.4), 2.32(3Hx2,s), 2.4-2.9(8H,m), 3.5-3.7(4H,m),                  3.83(3H,s), 4.0-                      399                                      4.3(2H,m), 6.8-7.0(2H,m), 7.3-7.5(2H,m)                                                                              247                                                                            233                              461     1.22(3H,t,J=7.4), 2.31(3Hx2,s), 2.2-3.0(8H,m), 3.1-3.4(2H,m),                  3.6-3.9(2H,m),                        429                                      3.85(3H,s), 3.88(3H,s), 4.0-4.3(2H,m), 6.7-7.2(3H,m)                                                                 277                                                                            263                                                                            164                              462     1.22(3H,t,J=7.4), 2.31(3Hx2,s), 2.2-3.0(8H,m), 3.1-3.4(2H,m),                  3.6-3.8(2H,m),                        429                                      3.82(3Hx2,s), 4.0-4.3(2H,m), 6.5-6.7(2H,m), 7.0-7.2(1H,m)                                                            277                                                                            263                                                                            164                              463     1.23(3H,t,J=7.4), 2.32(3Hx2,s), 2.4-3.0(8H,m), 3.7-3.9(4H,m),                  3.90(3H,s), 3.91                      429                                      (3H,s), 4.0-4.3(2H,m), 6.7-7.0(3H,m)  277                                                                            263                                                                            164                              464     1.22(3H,t,J=7.4), 2.32(3Hx2,s), 2.4-3.0(8H,m), 3.4-3.8(4H,m),                  3.87(3Hx2,s),                         459                                      4.0-4.3(2H,m), 6.61(2H,s)             306                                                                            195                              465     1.17(3H,t,J≈7.4), 2.27(3Hx2,s), 2.4-2.9(8H,m),                         2.9-3.1(4H,m), 3.9-4.2(2H,m),         441                                      7.4-7.8(4H,m)                         439                                                                            287                                                                            283                              467     1.18(3Hx2,t,J≈7.4), 2.3-2.8(14H,m), 3.51(2H,s),                        3.9-4.2(2H,m), 4.03(2H,s), 7.1        481(M.sup.+ + 1)                                                                      0.42                              -7.4(9H,m)                            479                              468     1.19(3H,t,J≈7.4), 1.20(3H,t,J≈7.4),                            2.3-2.8(14H,m), 3.58(2H,s), 3.8-4.0(2H,m),                                                                           526(M.sup.+ + 1)                         4.05(2H,s), 4.1-4.3(2H,m), 7.0-7.5(2H,m), 7.26(4H,s),                          8.17(2H,d,J=8.8)                      524                                                                            247                              470     1.6-2.0(4H,m), 2.4-2.8(10H,m), 3.5-3.8(4H,m), 3.9-4.2(2H,m),                   4.09(2H,s), 7.0-                      354(M.sup.+ + 1)                         7.5(5H,m)                             114                              471     1.6-2.0(4H,m), 2.3-2.8(14H,m), 3.50(2H,s), 3.9-4.1(2H,m),                      4.09(2H,s), 7.1-7.5                   443(M.sup.+ + 1)                         (10H,m)                               189                              472     1.6-2.0(4H,m), 2.5-2.9(1oH,m), 3.0-3.3(4H,m), 3.9-4.2(2H,m),                   4.10(2H,s), 6.7-                      429(M.sup.+ + 1)                         7.5(10H,m)                            175                              473     1.6-2.0(4H,m), 2.3-2.8(14H,m), 3.45(2H,s), 3.9-4.1(2H,m),                      4.09(2H,s), 7.1-7.5                   479(M.sup.+ + 1)                         (5H,m), 7.25(4H,s)                    477                                                                            223                              474     1.6-2.0(4H,m), 2.3-2.8(14H,m), 3.44(2H,s), 3.79(3H,s),                         3.9-4.1(2H,m), 4.09(                  473(M.sup.+ + 1)                         2H,s), 6.84(2H,d,J≈8.8), 7.0-7.5(7H,m)                                                                       219                              475     1.6-2.0(4H,m), 2.3-2.8(14H,m), 3.46(2H,s), 3.9-4.1(2H,m),                      4.09(2H,s), 6.8-7.5                   461(M.sup.+ + 1)                         (9H,m)                                207                              476     1.6-1.9(4H,m), 2.4-2.8(14H,m), 2.9-3.2(4H,m), 4.6-4.8(4H,m),                   3.9-4.2(2H,m),                        368(M.sup.+ + 1)                         7.1-7.4(5H,m)                         114                              477     1.6-1.9(4H,m), 2.4-2.8(14H,m), 2.9-3.2(4H,m), 3.52(2H,s),                      3.9-4.2(2H,m), 7.1-                   457(M.sup.+ + 1)                         7.4(10H,m)                            189                              478     1.6-2.0(4H,m), 2.4-2.9(10H,m), 2.9-3.4(8H,m), 4.0-4.2(2H,m),                   6.7-7.4(10H,m)                        443(M.sup.+ + 1)                                                               175                              479     1.6-2.0(4H,m), 2.3-2.8(14H,m), 2.9-3.2(4H,m), 3.47(2H,s),                      3.9-4.2(2H,m), 7.0-                   493(M.sup.+ + 1)                         7.4(5H,m), 7.26(4H,s)                 491                                                                            236                                                                            223                              480     1.6-2.0(4H,m), 2.3-2.8(14H,m), 2.9-3.2(4H,m), 3.45(2H,s),                      3.79(3H,s), 3.9-4.2                   407(M.sup.+ + 1)                         (2H,m), 6.92(2H,d,J≈8.8), 7.0-7.4(7H,m)                                                                      232                                                                            219                              481     1.23(3H,t,J=7.4), 1.6-2.0(4H,m), 2.3-3.0(12H,m), 3.5-3.8(4H,m),                3.9-4.2(2H,m)                         292(M.sup.+ + 1)                 482     1.23(3H,t,J=7.4), 1.6-2.0(4H,m), 2.3-3.0(16H,m), 3.47(2H,s),                   3.9-4.2(2H,m),                        417(M.sup.+ + 1)                         7.27(4H,s)                            415                                                                            223                              483     1.23(3H,t,J=7.4), 1.6-2.0(4H,m), 2.4-3.0(16H,m), 3.52(2H,s),                   3.9-4.2(2H,m),                        381(M.sup.+ + 1)                         7.2-7.3(5H,m)                         189                              484     1.24(3H,t,J=7.4), 1.6-2.0(4H,m), 2.6-3.0(12H,m), 3.1-3.3(4H,m),                4.0-4.3(2H,m),                        367(M.sup.+ + 1)                         6.7-7.4(5H,m)                         175                              485     1.23(3H,t,J=7.4), 1.6-2.0(6H,m), 2.4-3.0(16H,m), 3.59(2H,s),                   3.9-4.2(2H,m),                        431(M.sup.+ + 1)                         7.27(4H,s)                            429                                                                            237                              486     1.22(3H,t,J=7.4), 1.6-2.0(4H,m), 2.3-3.0(16H,m), 3.47(2H,s),                   3.80(3H,s), 3.9-                      411(M.sup.+ + 1)                         4.2(2H,m), 6.84(2H,d,J=8.8), 7.23(2H,d,J=8.8)                                                                        219                              487     0.88(3H,t,J≈6), 1.1-1.5(20H,m), 1.5-2.0(10H,m),                        2.4-2.9(14H,m), 3.51(2H,s),           549(M.sup.+ + 1)                         3.9-4.2(2H,m), 7.29(5H,s)             202                                                                            121                              488     0.88(3H,t,J≈6), 1.1-1.5(22H,m), 1.5-2.0(10H,m),                        2.5-3.0(14H,m), 3.72(2H,s),           608(M.sup.+ + 1)                         3.9-4.2(2H,m), 7.51(2H,d,J≈8.8), 8.17(2H,d,J=8.8)                                                            473                              489     0.88(3H,t,J≈6), 1.1-1.5(22H,m), 1.5-2.0(10H,m),                        2.4-2.9(14H,m), 3.54(2H,s),           599                                      3.9-4.2(2H,m), 7.27(4H,s)             597                              490     0.87(3H,t,J≈6), 1.1-1.5(22H,m), 1.5-2.0(10H,m),                        2.5-3.0(14H,m), 3.59(2H,s),           593(M.sup.+ + 1)                         3.80(3H,s), 3.9-4.2(2H,m), 6.84(2H,d,J=8.8), 7.24(2H,d,J=8.8)                                                        246                                                                            101                              611     2.30(3H,s), 2.34(3H,s), 2.4(3H,s), 2.5-3.0(9H,m),                                                                    250(M.sup.+ + 1)                                                                      0.04                      612     2.44(3Hx2,s), 3.91(2H,t,J≈6.3), 4.43(2H,t,J≈6.3),              8.1-8.3(5H,m)                         265 263                                                                               0.79                                                                    (M.sup.+ + 1)                    613     2.33(3Hx2,s), 3.80(2H,t,J=5.4), 4.09(2H,s), 4.29(2H,t,J=5.4),                  7.1-7.5(5H,m)                         278 276                                                                        (M.sup.+ + 1)                    614     0.99(3H,t,J=7.3), 1.5-1.9(6H,m), 2.5-2.9(6H,m), 3.38(1H,bs),                   3.8-4.0(2H,m),                        237(M.sup.+ + 1)                                                                      0.34                              4.1-4.3(2H,m)                         164                              615     0.99(3H,t,J=7.3), 1.5-2.0(6H,m), 2.3-2.8(6H,m), 3.1-3.4(2H,m),                 4.0-4.2(2H,m),                        329(M.sup.+ + 1)                         7.1-7.6(5H,m)                         319                              616     0.99(3H,t,J=7.2), 1.5-2.0(2H,m), 2.33(3Hx2,s), 2.74(2H,t,J=7.7),               3.8-4.0(2H,                           211(M.sup.+ + 1)                                                                      0.29                              m), 4.1-4.3(2H,m)                                                      617     0.94(3Hx2,d,J=6.6), 1.8-2.4(1H,m), 2.33(3Hx3,s),                               2.64(2H,d,J=7.1), 3.8-4.0(2H,         225(M.sup.+ + 1)                                                                      0.29                              m), 4.1-4.3(2H,m)                                                      618     0.95(3Hx2,d,J=6.6), 1.6-2.0(4H,m), 2.0-2.4(1H,m), 2.5-2.8(6H,m),               3.8-4.0(2H,                           251(M.sup.+ + 1)                                                                      0.34                              m), 4.1-4.3(2H,m)                                                      619     0.93(3Hx2,d,J= 6.4), 2.0-2.4(1H,m), 2.31(2Hx2,s), 2.3-2.7(12H,m),              3.46(2H,s),                           401(M.sup.+ + 1)                                                                      0.34                              3.9-4.3(2H,m), 6.8-7.1(2H,m), 7.1-7.4(2H,m)                                                                          207                              620     1.00(3H,t,J=7.3), 1.21(3Hx2,t,J=7.5), 1.5-1.9(2H,m),                           2.4-2.9(6H,m), 3.9-4.0(               239(M.sup.+ + 1)                                                                      0.44                              2H,m), 4.1-4.3(2H,m)                                                   621     0.94(3H,t,J=7.0), 1.2-2.0(8H,m), 2.5-2.9(6H,m), 3.8-4.0(2H,m),                 4.0-4.3(2H,m)                         251(M.sup.+ + 1)                                                                      0.32                      622     1.20(3Hx2,d,J=6.8), 2.32(3Hx2,s), 3.41(1H,sept,J=6.8),                         3.8-4.1(2H,m), 4.1-4.3(               211(M.sup.+ + 1)                                                                      0.36                              m)                                                                     623     0.79(3H,t,J=7.3), 1.18*3H,d,J=6.9), 1.3-2.0(3H,t,J=7.4),                       1.11(3H,d,J=6.9),                     225(M.sup.+ + 1)                                                                      0.35                              1.3-2.0(2H,m), 2.32(3Hx2,s), 3.22(1H,sept,J=6.9),                              3.94(2H,t,J=5.2),                                                              4.26(2H,t,J= 5.2)                                                      624     0.93(3H,t,J=6.7), 1.2-2.0(4H,m), 2.33(3Hx2,s), 2.77(2H,t,J=5.6),               3.7-4.0(2H,                           225(M.sup.+ + 1)                                                                      0.33                              m), 4.1-4.3(2H,m)                                                      625     1.1-1.4(12H,m), 2.55(2H,t,J=7.6), 2.72(2H,t,J=7.6),                            3.41(1H,sept,J=6.9), 3.72             239(M.sup.+ + 1)                                                                      0.40                              (1H,bs), 3.8-4.1(2H,m), 4.26(2H,t,J=5.1)                                                                             195                              626     0.95(3Hx2,d,J=6.4), 1.21(3Hx2,t,J=7.4), 2.0-2.4(1H,m),                         2.4-2.9(6H,m), 3.8-4.0(               253(M.sup.+ + 1)                                                                      0.34                              2H,m), 4.1-4.3(2H,m)                  210                              627     0.88(3H,t,J=7.5), 1.0-1.4(9H,m), 1.2-2.2(2H,m), 2.4-2.8(4H,m),                 3.1-3.4(1H,m),                        253(M.sup.+                                                                           0.34                              3.8-4.0(2H,m), 4.1-4.3(2H,m)                                           628     0.97(3Hx2,d,J=6.4), 1.21(3Hx2,t,J=7.4), 1.2-1.9(4H,m),                         2.4-2.9(6H,m), 3.8-4.0(               253(M.sup.+ + 1)                                                                      0.37                              2H,m)                                 210                              629     1.1-1.4(9H,m), 2.4-2.6(6H,m), 3.93(3H,t,J=5.1),                                                                      225(M.sup.+ + 1)                                                                      0.33                                                                    130                              630     1.21(3Ht,J=7.5), 2.32(3Hx2,s), 2.77(2H,q,J=7.5),                               3.92(2H,t,J=5.0), 4.24(2H,t,          197(M.sup.+ + 1)                         J=5.0)                                153                              631     0.89(3H,t,J=6.6), 1.2-1.9(10H,m), 2.5-2.9(6H,m), 3.8-4.0(2H,m),                4.0-4.3(3H,m)                         265(M.sup.+ + 1)                                                                      0.32                                                                    239                                                                            208                              632     0.88(3H,t,J=6.6), 1.2-1.9(12H,m), 2.5-2.9(6H,m), 3.8-4.0(2H,m),                4.0-4.3(2H,m)                         265(M.sup.+ + 1)                                                                      0.33                                                                    219                                                                            208                              633     0.87(3H,t,J≈6), 1.1-2.0(14H,m), 2.5-2.9(6H,m),                         3.8-4.0(2H,m), 4.0-4.3(2H,m)          293(M.sup.+ + 1)                                                                      0.34                                                                    247                                                                            208                              634     0.87(3H,t,J≈6), 1.1-2.0(16H,m), 2.5-2.9(6H,m),                         3.8-4.0(2H,m), 4.0-4.3(2H,m)          307(M.sup.+ + 1)                                                                      0.38                                                                    208                              635     0.87(3H,t,J≈6), 1.1-2.0(18H,m), 2.5-2.9(6H,m),                         3.3(1H,bs), 3.8-4.0(2H,m), 4.0-       321(M.sup.+ + 1)                                                                      0.39                              4.3(2H,m)                                                              636     0.87(3H,t,J≈6), 1.2-2.0(20H,m), 2.5-2.9(6H,m),                         3.3(1H,bs), 3.8-4.0(2H,m), 4.1-       335(M.sup.+ + 1)                                                                      0.35                              4.3(2H,m)                             208                              637     0.88(3H,t,J≈6), 1.1-2.0(24H,m), 2.5-2.9(6H,m),                         3.34(1H,bs), 3.8-4.0(2H,m),           363(M.sup.+ + 1)                                                                      0.41                              4.0-4.3(2H,m)                                                          638     0.88(3H,t,J≈6), 1.1-2.0(28H,m), 2.5-2.9(6H,m),                         3.20(1H,bs), 3.8-4.0(2H,m),           391(M.sup.+ + 1)                                                                      0.41                              4.0-4.3(2H,m)                                                          639     0.88(3H,t,J≈6), 1.1-2.0(32H,m), 2.5-2.9(6H,m),                         3.25(1H,bs), 3.8-4.0(2H,m),           419(M.sup.+ + 1)                                                                      0.46                              4.0-4.3(2H,m)                                                          640     1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.58(2H,q,J=7.6),                          2.68(2H,q,J=7.6), 3.89(               286(M.sup.+ + 1)                                                                      0.31                              2H,t,J≈6.6), 4.08(2H,s), 4.19(2H,t,J≈6),                       7.0-7.4(5H,m)                                                          641     1.19(3H,t,J≈7.7), 1.20(3H,t,J=7.7), 2.58(2H,q,J=7.7),                  2.69(2H,q,J=7.7), 3.8-                323    0.26                              4.0(2H,m), 4.05(2H,s), 4.21(2H,t,J=5.2), 7.1-7.4(4H,m)                                                               321                              642     2.30(3H,s), 2.34(3H,s), 2.41(3H,s), 2.5-3.0(8H,m),                                                                   250(M.sup.+ + 1)                                                                      0.06                      643     1.6-1.9(4H,m), 2.5-2.8(4H,m), 3.7-4.0(2H,m), 4.09(2H,s),                       4.0-4.2(2H,m), 7.0-                   255(M.sup.+ + 1)                         7.4(5H,m)                                                              644     1.6-2.0(4H,m), 2.5-2.8(4H,m), 3.79(2H,t,J≈7), 4.10(2H,s),              4.23(2H,t,J≈7), 7.0-          305                                      7.5(5H,m)                             303                                                                            267                                                                            239                              645     1.6-2.0(4H,m), 2.5-2.8(4H,m), 3.03(2Hx2,s), 3.90(2H,t,J≈5)             , 4.18(2H,t,J≈5),             299                                      7.0-7.4(5H,m)                                                          646     1.22(3H,t,J≈ 7.3), 1.7-4.0(4H,m), 2.6-2.8(4H,m),                       3.78(2H,q,J≈7.3), 3.7-4.0(2H, 223                                      m), 4.0-4.3(2H,m)                                                      647     1.19(3H,t,J≈7.7), 1.21(3H,t,J≈7.7),                            2.61(2H,q,J≈7.7), 2.74(2H,q,J≈7.7),                                                                  343-                                     4.4(4H,m), 7.1-7.5(4H,m)              341                                                                            339(M.sup.+ + 1)                 __________________________________________________________________________ 

What is claimed is:
 1. A compound of the formula ##STR424## wherein A is lower alkylene R₁ is selected from the group consisting of alkyl, phenyl-lower alkyl, and substituted phenyl-lower alkyl; R₂ and R₃ are each lower alkyl;and R is selected from the group consisting of 1-methyltetrazole-5-yl-thio, 1-imidazolyl, morpholino, ##STR425## in which R₅ is hydrogen, lower alkyl or aryl, R⁶ is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl, Ar is phenyl or phenyl substituted with C₁₋₃ alkyl, halogen, nitro, or lower alkoxy, A, R₁, R₂ and R₃ are as defined above, m is an integer from 4-6, and n is 2 or 3; and pharmaceutically acceptable salts thereof.
 2. The compound of claim 1 wherein R is 1-methyltetrazole-5-yl-thio.
 3. The compound of claim 1 wherein R is 1-imidazolyl.
 4. The compound of claim 1 wherein R is ##STR426##
 5. The compound of claim 1 wherein R is ##STR427## where n is an integer in the range of 2 to
 3. 6. The compound of claim 5 where n is
 2. 7. The compound of claim 1 wherein R is morpholino.
 8. The compound of claim 1 wherein R is ##STR428## where m is an integer in the range of 4 to
 6. 9. The compound of claim 8 wherein m is 4 or
 5. 10. The compound of claim 1 wherein R is ##STR429## where R₆ is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl. 